Bicyclic pyrimidine derivatives and their use as anti-coagulants

ABSTRACT

This invention is directed to bicyclic pyrimidine derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.

FIELD OF THE INVENTION

The present invention is directed to bicyclic pympirine derivatives andtheir pharmaceutically acceptable salts, which inhibit the enzyme,factor Xa, thereby being useful as anti-coagulants. It also relates topharmaceutical compositions containing the derivatives or theirpharmaceutically acceptable salts, and methods of their use.

BACKGROUND OF THE INVENTION

Factor Xa is a member of the trypsin-like serine protease class ofenzymes. A one-to-one binding of factors Xa and Va with calcium ions andphospholipid forms the prothrombinase complex which converts prothrombinto thrombin. Thrombin, in turn, converts fibrinogen to fibrin whichpolymerizes to form insoluble fibrin.

In the coagulation cascade, the prothrombinase complex is the convergentpoint of the intrinsic (surface activated) and extrinsic (vesselinjury-tissue factor) pathways (Biochemistry (1991), Vol. 30, p. 10363;and Cell (1988), Vol. 53, pp. 505-518). The model of the coagulationcascade has been refined further with the discovery of the mode ofaction of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology(1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serineprotease inhibitor with three Kunitz-like serpin domains which competeswith factor Va for free factor Xa. Once formed, the binary complex offactor Xa and TFPI becomes a potent inhibitor of the factor VIIa andtissue factor complex.

Factor Xa can be activated by two distinct complexes, by tissuefactor-VIIa complex on the "Xa burst" pathway and by the factorIXa-VIIIA complex (TENase) of the "sustained Xa" pathway in thecoagulation cascade. After vessel injury, the "Xa burst" pathway isactivated via tissue factor (TF). Up regulation of the coagulationcascade occurs via increased factor Xa production via the "sustained Xa"pathway. Down regulation of the coagulation cascade occurs with theformation of the factor Xa-TFPI complex, which not only removes factorXa but also inhibits further factor formation via the "Xa burst"pathway. Therefore, the coagulation cascade is naturally regulated byfactor Xa.

The primary advantage of inhibiting factor Xa over thrombin in order toprevent coagulation is the focal role of factor Xa versus the multiplefunctions of thrombin. Thrombin not only catalyzes the conversion offibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factorXI to XIa, but also activates platelets, is a monocyte chemotacticfactor, and mitogen for lymphocytes and smooth muscle cells. Thrombinactivates protein C, the in vivo anti-coagulant inactivator of factorsVa and VIIIa, when bound to thrombomodulin. In circulation, thrombin israpidly inactivated by antithrombin III (ATIII) and heparin cofactor II(HCII) in a reaction which is catalyzed by heparin or otherproteoglycan-associated glycosaminoglycans, whereas thrombin in tissuesis inactivated by the protease, nexin. Thrombin carries out its multiplecellular activation functions through a unique "tethered ligand"thrombin receptor (Cell (1991), Vol. 64, p. 1057), which requires thesame anionic binding site and active site used in fibrinogen binding andcleavage and by thrombomodulin binding and protein C activation. Thus, adiverse group of in vivo molecular targets compete to bind thrombin andthe subsequent proteolytic events will have very different physiologicalconsequences depending upon which cell type and which receptor,modulator, substrate or inhibitor binds thrombin.

Published data with the proteins antistasin and tick anti-coagulantpeptide (TAP) demonstrate that factor Xa inhibitors are efficaciousanti-coagulants (Thrombosis and Haemostasis (1992), Vol. 67, pp.371-376; and Science (1990), Vol. 248, pp. 593-596).

The active site of factor Xa can be blocked by either a mechanism-basedor a tight binding inhibitor (a tight binding inhibitor differs from amechanism-based inhibitor by the lack of a covalent link between theenzyme and the inhibitor). Two types of mechanism-based inhibitors areknown, reversible and irreversible, which are distinguished by ease ofhydrolysis of the enzyme-inhibitor link (Thrombosis Res (1992), Vol. 67,pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). Aseries of guanidino compounds are examples of tight-binding inhibitors(Thrombosis Res. (1980), Vol. 19, pp. 339-349).Arylsulfonyl-arginine-piperidinecarboxylic acid derivatives have alsobeen shown to be tight-binding inhibitors of thrombin (Biochem. (1984),Vol. 23, pp. 85-90), as well as a series of arylamidine-containingcompounds, including 3-amidinophenylaryl derivatives (Thrombosis Res.(1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones(Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compoundsdemonstrate poor selectivity for factor Xa.

Related Disclosures

European Published Patent Application 0 540 051 (Nagahara et al.)describes aromatic amidine derivatives which are stated to be capable ofshowing a strong anticoagulant effect through reversible inhibition offactor Xa.

The synthesis of α,α'-bis(amidinobenzylidene)cycloalkanones andα,α'-bis(amidino-benzyl)cycloalkanones is described in Pharmazie (1977),Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as beingserine protease inhibitors.

SUMMARY OF THE INVENTION

This invention is directed to compounds or their pharmaceuticallyacceptable salts which inhibit human factor Xa and are therefore usefulas pharmacological agents for the treatment of disease-statescharacterized by thrombotic activity.

Accordingly, in one aspect, this invention provides compounds selectedfrom the group consisting of the following formulae: ##STR1## wherein: Ais --O--, --N(R⁵)--, or --S(O)_(n) -- (where n is 0, 1 or 2);

Z¹ and Z² are independently --O--, --N(R⁵)-- or --OCH₂ --;

R¹ and R⁴ are each independently hydrogen, halo, alkyl, --OR⁸,--C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --N(R⁸)C(O)R⁹, or --N(H)S(O)₂ R¹¹ ;

R² is --C(NH)NH₂, --C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹¹,--C(NH)N(H)C(O)R⁸, --C(NH)N(H)S(O)₂ R¹¹, or --C(NH)N(H)C(O)N(H)R⁸ ;

R³ is halo, alkyl, haloalkyl, cyano, ureido, guanidino, --OR⁸,--C(NH)NH₂, --C(NH)N(H)OR⁸, --C(O)N(R⁸)R⁹, --R¹⁰ --C(O)N(R⁸)R⁹,--CH(OH)C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --R¹⁰ --N(R⁸)R⁹, --C(O)OR⁸, --R¹⁰--C(O)OR⁸, --N(R⁸)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionallysubstituted by alkyl), (1,2)-imidazolyl (optionally substituted byalkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl);

each R⁵ is hydrogen, alkyl, aryl (optionally substituted by halo, alkyl,hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl);

R⁶ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,cycloalkyl, cycloalkylalkyl, --C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --R¹⁰--C(O)N(R⁸)R⁹, --C(O)--R¹⁰ --N(R⁸)R⁹, --R¹⁰ --C(O)R⁸, --R¹⁰--C(O)N(R⁸)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(OR⁹)--R¹⁰ --N(R⁸)(R⁹),--C(R⁸)(OR⁸)C(O)OR⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸,--R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --C(R⁸)(OR⁸)R⁹, --R¹⁰ --N(R⁸)R⁹, --R¹⁰--N(R⁸)C(O)OR¹¹, --R¹⁰ --N(R⁸)C(O)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)R¹¹, --R¹⁰--N(R⁸)S(O)₂ R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹,--R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)N(R⁸)R⁹, --R¹⁰ --N(R⁸)--R¹⁰--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --N(R⁸)S (O)R⁹, --R¹⁰ --OR⁸, --R¹⁰--ON(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ --OS(O)₂ OR⁸, --R¹⁰ --P(O)(OR⁸)R⁹, --R¹⁰--OP(O)(OR⁸)₂, --R¹⁰ --P(O)(OR⁸)₂, --R¹⁰ --SR⁸, --R¹⁰ --S--R¹⁰--C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)R⁹, --R¹⁰ --S--R¹⁰--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)C(O)OR⁸, --R¹⁰ --S--R¹⁰--N(R⁸)C(O)R⁸, --R¹⁰ --S--S--R¹⁰ --C(R⁸)(N(R⁸)R⁹ C(O)OR⁸, --R¹⁰--SC(O)N(R⁸)R⁹, --R¹⁰ --SC(S)N(R⁸)R⁹, --R¹⁰ --S(O)R⁸, --R¹⁰ --S(O)₂ R¹¹,--R¹⁰ --S(O)OR⁸, --R¹⁰ --S(O)₂ OR⁸, --R¹⁰ --S(O)₂ N(R⁸)R⁹, --R¹⁰--S(O)(NR⁸)R⁹ ;

or R⁶ is aryl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl,haloalkoxy, --OR⁸, --SR⁸, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂);

or R⁶ is aralkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl,haloalkoxy, --OR⁸, --SR⁸, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂);

or R⁶ is heterocyclyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy, aralkyl, --OR⁸, --C(O)OR⁸, --N(R⁸)R⁹,--C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂);

or R⁶ is heterocyclylalkyl (where the heterocyclyl radical is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy, aralkyl, --OR⁸, --SR⁸,--C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹) --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂);

or R⁶ is adamantyl (optionally substituted by alkyl, halo, haloalkyl,haloalkoxy, --OR⁸, --SR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂);

or R⁶ is adamantylalkyl (where the adamantyl radical is optionallysubstituted by alkyl, halo, haloalkyl, haloalkoxy,--OR⁸, --SR⁸,--C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸) R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂);

R⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl;

each R⁸ and R⁹ is independently hydrogen, alkyl, aryl (optionallysubstituted by halo, alkyl, hydroxy, alkoxy, aralkoxy, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl);

R¹⁰ is a straight or branched alkylene chain; and

R¹¹ is alkyl, aryl (optionally substituted by halo, alkyl, hydroxy,alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl);

as a single stereoisomer or a mixture thereof; or a pharmaceuticallyacceptable salt thereof.

In another aspect, this invention provides compositions useful intreating a human having a disease-state characterized by thromboticactivity, which composition comprises a therapeutically effective amountof a compound of the invention as described above, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect, this invention provides a method of treating a humanhaving a disease-state characterized by thrombotic activity, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of treating a humanhaving a disease-state alleviated by the inhibition of factor Xa, whichmethod comprises administering to a human in need thereof atherapeutically effective amount of a compound of the invention asdescribed above.

In another aspect, this invention provides a method of inhibiting humanfactor Xa in vitro or in vivo by the administration of a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated

"Alkyl" refers to a straight or branched chain monovalent or divalentradical consisting solely of carbon and hydrogen, containing nounsaturation and having from one to six carbon atoms, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.

"Alkenyl" refers to a straight or branched chain monovalent or divalentradical consisting solely of carbon and hydrogen, containing at leastone double bond and having from one to six carbon atoms, e.g., ethenyl,prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

"Alkynyl" refers to a straight or branched chain monovalent or divalentradical consisting solely of carbon and hydrogen, containing at leastone triple bond and having from one to six carbon atoms, e.g., ethynyl,prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl, and the like.

"Alkoxy" refers to a radical of the formula --OR_(a) where R_(a) isalkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy(iso-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (t-butoxy), andthe like.

"Alkoxycarbonyl" refers to a radical of the formula --C(O)OR_(a) whereR_(a) is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl, iso-propoxycarbonyl, t-butoxycarbonyl, and the like.

"Alkylene" refers to straight or branched chain divalent radicalconsisting solely of carbonyl and hydrogen, containing no unsaturationand having from one to six carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like.

"Amidino" refers to the radical --C(NH)--NH₂.

"Aminocarbonyl" refers to the radical --C(O)NH₂.

"Aryl" refers to a phenyl or naphthyl radical.

"Aralkyl" refers to a radical of the formula --R_(a) R_(b) where R_(a)is alkyl as defined above and R_(b) is aryl as defined above, e.g.,benzyl.

"Aralkoxy" refers to a radical of the formula --OR_(c) where R_(c) isaralkyl as defined above, e.g., benzyloxy, and the like.

"Cycloalkyl" refers to a stable 3- to 7-membered monocyclic cyclicradical which is saturated, and which consist solely of carbon andhydrogen atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and the like.

"Cycloalkylalkyl" refers to a alkyl radical, as defined above,substituted by a cycloalkyl radical, as defined above, e.g.,(cyclobutyl)methyl, 2-(cyclopentyl)ethyl, 3-(cyclohexyl)propyl, and thelike.

"Dialkylamino" refers to a radical of the formula --NR_(a) R_(a) whereeach R_(a) is independently an alkyl radical as defined above, e.g.,dimethylamino, methylethylamino, diethylamino, dipropylamino,ethylpropylamino, and the like.

"Dialkylaminocarbonyl" refers to a radical of the formula --C(O)NR_(a)R_(a) where each R_(a) is independently an alkyl radical as definedabove, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl,diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl,and the like.

"Halo" refers to bromo, iodo, chloro or fluoro.

"Haloalkyl" refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl,3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.

"Haloalkenyl" refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,2-difluoroethenyl, 3-bromo-2-fluoroprop-1-enyl, and the like.

"Haloalkoxy" refers to a radical of the formula --OR_(f) where R_(f) ishaloalkyl as defined above, e.g., trifluoromethoxy, difluoromethoxy,trichloromethoxy, 2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy,3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.

"Heterocyclyl" refers to a stable 3- to 10-membered monocyclic orbicyclic radical which is either saturated or unsaturated, and whichconsists of carbon atoms and from one to three heteroatoms selected fromthe group consisting of nitrogen, oxygen and sulfur, and wherein thenitrogen, carbon or sulfur atoms may be optionally oxidized, and thenitrogen atom may be optionally quaternized. The heterocyclyl radicalmay be attached to the main structure at any heteroatom or carbon atomwhich results in the creation of a stable structure. Examples of suchheterocyclic radicals include, but are not limited to, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl,pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,isoindolyl, indolinyl, isoindolinyl, octahydroindolyl,octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl,benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl. Preferred heterocyclylradicals in this invention are indolyl, imidazolyl, thiazolyl,isoxazolyl, triazolyl, pyridinyl, thienyl, benzothienyl, furyl, and3,4-dihydro-2,3-dioxo-1(2H)-pyrimidinyl.

"Heterocyclylalkyl" refers to a radical of the formula --R_(a) R_(g)where R_(a) is an alkyl radical as defined above and R_(g) is aheterocyclyl radical as defined above, e.g., indolinylmethyl orimidazolylmethyl, and the like.

"(1,2)-Imidazolyl" refers to an imidazolyl radical attached at eitherthe 1- or 2-position.

"(1,2)-Imidazolinyl" refers to a 4,5-dihydroimidazolyl radical attachedat either the 1- or the 2-position.

"Monoalkylamino" refers to a radical of the formula --NHR_(a) whereR_(a) is an alkyl radical as defined above, e.g., methylamino,ethylamino, propylamino, and the like.

"Monoalkylaminocarbonyl" refers to a radical of the formula--C(O)NHR_(a) where R_(a) is an alkyl radical as defined above, e.g.,methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and thelike.

"(1,2)-Tetrahydropyrimidinyl" refers to a tetrahydropyrimidinyl attachedat either the 1- or 2-position.

"Adamantylalkyl" refers to a radical of the formula --R_(a) R_(h) whereR_(a) is an alkyl radical as defined above, and R_(h) is an adamantylradical, e.g., adamantylmethyl, 2-adamantylethyl, and the like.

"Optional" or "optionally" means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, "optionally substituted aryl" means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

"Pharmaceutically acceptable salt" includes both acid and base additionsalts.

"Pharmaceutically acceptable acid addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, andorganic acids such as acetic acid, trifluoroacetic acid, propionic acid,glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like.

"Pharmaceutically acceptable base addition salt" refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine,procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline and caffeine.

"Therapeutically effective amount" refers to that amount of a compoundof the invention which, when administered to a human in need thereof, issufficient to effect treatment, as defined below, for disease-statescharacterized by thrombotic activity. The amount of a compound of theinvention which constitutes a "therapeutically effective amount" willvary depending on the compound, the disease-state and its severity, andthe age of the human to be treated, but can be determined routinely byone of ordinary skill in the art having regard to his own knowledge andto this disclosure.

"Treating" or "treatment" as used herein cover the treatment of adisease-state in a human, which disease-state is characterized bythrombotic activity; and include:

(i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it;

(ii) inhibiting the disease-state, i.e., arresting its development; or

(iii) relieving the disease-state, i.e., causing regression of thedisease-state.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms in their structure. Thecompounds of the invention and their pharmaceutically acceptable saltsmay therefore exist as single stereoisomers, racemates, and as mixturesof enantiomers and diastereomers. All such single stereoisomers,racemates and mixtures thereof are intended to be within the scope ofthis invention.

It is noted that when R¹ is the same substituent as R⁴, R² is the samesubstituent as R³, and Z¹ and Z² are the same, compounds of formula (I)are the same as compounds of formula (II).

For compounds of the invention, it is preferred that R¹ is at the2-position of the phenyl group; that R² is at the 3-, 4-, or 5-positionof the phenyl group; that R³ is at the 3-, 4- or 5- position of thephenyl group; and that R⁴ is at the 2-position of the phenyl group.

The nomenclature used herein is a modified form of the I.U.P.A.C. systemwherein the compounds of the invention are named, depending on what "A"is, as derivatives of 6(5H)-pterdinones, 5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-ones, or 5H-pyrimido 4,5-b! 1,4!thiazin-6(7H)-ones. Forexample, a compound of formula (I) wherein A is --N(H)--; Z¹ and Z² areboth --O--; R¹ is hydrogen; R² is --C(NH)NH₂ ; R³ is --C(O)N(CH₃)₂ ; R⁴is hydrogen; R⁵ is hydrogen; R⁶ is benzyl; and R⁷ is hydrogen; e.g.:##STR2## is named herein as2-(2-hydroxy-5-amidinophenoxy)-4-(3-dimethylaminocarbonylphenoxy)-7-benzyl-1,7-dihydro-6(5H)-pteridinone.

Utility and Administration

A. Utility

The compounds of the invention are inhibitors of factor Xa and thereforeuseful in disease-states characterized by thrombotic activity based onfactor Xa's role in the coagulation cascade (see Background of theInvention above). A primary indication for the compounds is prophylaxisfor long term risk following myocardial infarction. Additionalindications are prophylaxis of deep vein thrombosis (DVT) followingorthopedic surgery or prophylaxis of selected patients following atransient ischemic attack. The compounds of the invention may also beuseful for indications in which coumadin is currently used, such as forDVT or other types of surgical intervention such as coronary arterybypass graft and percutaneous transluminal coronary angioplasty. Thecompounds are also useful for the treatment of thrombotic complicationsassociated with acute promyelocytic leukemia, diabetes, multiplemyelomas, disseminated intravascular coagulation associated with septicshock, purpura fulminanas associated infection, adult respiratorydistress syndrome, unstable angina, and thrombotic complicationsassociated with aortic valve or vascular prosthesis. The compounds arealso useful for prophylaxis for thrombotic diseases, in particular inpatients who have a high risk of developing such disease.

In addition, the compounds of the invention are useful as in vitrodiagnostic reagents for selectively inhibiting factor Xa withoutinhibiting other components of the coagulation cascade.

B. Testing

The primary bioassays used to demonstrate the inhibitory effect of thecompounds of the invention on factor Xa are simple chromogenic assaysinvolving only serine protease, the compound of the invention to betested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol.16, pp. 245-254). For example, four tissue human serine proteases can beused in the primary bioassay, free factor Xa, prothrombinase, thrombin(IIa) and tissue plasminogen activator (tPA). The assay for TPA has beensuccessfully used before to demonstrate undesired side effects in theinhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993),Vol. 36, pp. 314-319). Another bioassay useful in demonstrating theutility of the compounds of the invention in inhibiting factor Xademonstrates the potency of the compounds against free factor Xa incitrated plasma. For example, the anticoagulant efficacy of thecompounds of the invention will be tested using either the prothrombintime (PT), or activated partial thromboplastin time (aPTT) whileselectivity of the compounds is checked with the thrombin clotting time(TCT) assay. Correlation of the K_(i) in the primary enzyme assay withthe K_(i) for free factor Xa in citrated plasma will screen againstcompounds which interact with or are inactivated by other plasmacomponents. Correlation of the K_(i) with the extension of the PT is anecessary in vitro demonstration that potency in the free factor Xainhibition assay translates into potency in a clinical coagulationassay. In addition, extension of the PT in citrated plasma can be usedto measure duration of action in subsequent pharmacodynamic studies.

For further information on assays to demonstrate the activity of thecompounds of the invention, see R. Lottenberg et al., Methods inEnzymology (1981), Vol. 80, pp. 341-361, and H. Ohno et al., ThrombosisResearch (1980), Vol. 19, pp. 579-588.

C. General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally,topically, transdermally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. Preferably, the composition will be about 5%to 75% by weight of a compound(s) of the invention, or apharmaceutically acceptable salt thereof, with the rest being suitablepharmaceutical excipients.

The preferred route of administration is oral, using a convenient dailydosage regimen which can be adjusted according to the degree of severityof the disease-state to be treated. For such oral administration, apharmaceutically acceptable composition containing a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, is formed bythe incorporation of any of the normally employed excipients, such as,for example, pharmaceutical grades of mannitol, lactose, starch,pregelatinized starch, magnesium stearate, sodium saccharine, talcum,cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propylgallate, and the like. Such compositions take the form of solutions,suspensions, tablets, pills, capsules, powders, sustained releaseformulations and the like.

Preferably such compositions will take the form of capsule, caplet ortablet and therefore will also contain a diluent such as lactose,sucrose, dicalcium phosphate, and the like; a disintegrant such ascroscarmellose sodium or derivatives thereof; a lubricant such asmagnesium stearate and the like; and a binder such as a starch, gumacacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, andthe like.

The compounds of the invention, or their pharmaceutically acceptablesalts, may also be formulated into a suppository using, for example,about 0.5% to about 50% active ingredient disposed in a carrier thatslowly dissolves within the body, e.g., polyoxyethylene glycols andpolyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc., a compound(s) of the invention(about 0.5% to about 20%), or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike, to thereby form a solution or suspension.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state alleviated by the inhibition of factor Xa inaccordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. Generally, a therapeutically effective daily dose is from about0.14 mg to about 14.3 mg/kg of body weight per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof; preferably,from about 0.7 mg to about 10 mg/kg of body weight per day; and mostpreferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day.For example, for administration to a 70 kg person, the dosage rangewould be from about 10 mg to about 1.0 gram per day of a compound of theinvention, or a pharmaceutically acceptable salt thereof, preferablyfrom about 50 mg to about 700 mg per day, and most preferably from about100 mg to about 500 mg per day.

Preferred Embodiments

Of the compounds of the invention as set forth above in the Summary ofthe Invention, a preferred group are those compounds wherein A is --O--or --N(R⁵)--; Z¹ and Z² are both --O--; R¹ and R⁴ are each independentlyhydrogen, halo or --OR⁸ ; R² is --C(NH)NH₂, --C(NH)N(H)S(O)₂ R¹¹ or--C(NH)N(H)C(O)N(H)R⁸ ; R³ is ureido, guanidino, --OR⁸, --C(O)N(R⁸)R⁹,--N(R⁸)R⁹, --C(O)OR⁸, --N(R⁸)C(O)R⁸, (1,2)-tetrahydropyrimidinyl(optionally substituted by alkyl), (1,2)-imidazolyl (optionallysubstituted by alkyl), or (1,2)-imidazolinyl (optionally substituted byalkyl); each R⁵ is hydrogen, alkyl, aryl (optionally substituted byhalo), or aralkyl (optionally substituted halo); R⁶ is hydrogen, alkyl,--R¹⁰ --C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --R¹⁰--N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ OR⁸, --R¹⁰ OP(O)(OR⁸)₂, --R¹⁰ --SR⁸, or--R¹⁰ --S(O)₂ R¹¹ ; or R⁶ is aryl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy and --OR⁸); or R⁶ is aralkyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy and --OR⁸); or R⁶ isheterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, haloalkoxyand --OR⁸); or R⁶ is heterocyclylalkyl (where the heterocyclyl radicalis optionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, haloalkoxy or --OR⁸); R⁷ ishydrogen, alkyl, cycloalkyl, aralkyl or aryl; each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl (optionally substituted by halo,alkyl, hydroxy or alkoxy), or aralkyl (optionally substituted by halo,alkyl, hydroxy or alkoxy); R¹⁰ is a straight or branched alkylene chain;and R¹¹ is alkyl, aryl (optionally substituted by halo, alkyl, hydroxyor alkoxy), or aralkyl (optionally substituted by halo, alkyl, hydroxyor alkoxy).

Of this group of compounds, a preferred subgroup of compounds is thatsubgroup wherein A is --N(R⁵)--; Z¹ and Z² are both --O--; R¹ and R⁴ areeach independently hydrogen or --OR⁸ ; R² is --C(NH)NH₂ ; R³ is--C(O)N(R⁸)R⁹, (1,2)-tetrahydropyrimidinyl (optionally substituted byalkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁵ ishydrogen, alkyl, aryl (optionally substituted by halo), or aralkyl(optionally substituted halo); R⁶ is hydrogen, alkyl, --R¹⁰ --C(O)OR⁸,--R¹⁰ --C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --R¹⁰ --N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹,--R¹⁰ OR⁸, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --SR₈, or --R¹⁰ --S(O)² R¹¹ ; orR⁶ is aralkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, haloalkoxyand --OR⁸); or R⁶ is imidazolylalkyl or indolylalkyl; R⁷ is hydrogen oralkyl; each R⁸ and R⁹ is independently hydrogen, alkyl, aryl, oraralkyl; R¹⁰ is a straight or branched alkylene chain; and R¹¹ is alkylor aryl.

Of this subgroup of compounds, a preferred class of compounds is thatclass wherein R¹ is --OR⁸ ; R² is --C(NH)NH₂ ; R³ is --C(O)N(R⁸)R⁹,(1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl); each R⁵ ishydrogen, alkyl, aryl or aralkyl; R⁶ is hydrogen, alkyl, --R¹⁰--C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --R¹⁰--N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ OR⁸, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --SR⁸, or--R¹⁰ --S(O)₂ R¹¹ ; or R⁶ is aralkyl (optionally substituted by one ormore substituents selected from the group consisting of methyl andhydroxy); or R⁶ is imidazolylalkyl or indolylalkyl; R⁷ is hydrogen oralkyl; each R⁸ and R⁹ is independently hydrogen, alkyl, aryl, oraralkyl; R¹⁰ is a straight or branched alkylene chain; and R¹¹ is alkylor aryl.

Of this class of compounds, a preferred subclass of compounds is thatsubclass wherein A is --N(H)--; Z¹ and Z² are both --O--; R¹ is hydroxy;R² is --C(NH)NH₂ ; R³ is --C(O)N(CH₃)₂ ; and R⁴, R⁵, R⁶, and R⁷ arehydrogen.

A preferred compound of this subclass of compounds is that compoundselected from formula (I), namely,2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone.

Another preferred compound of this subclass of compounds is thatcompound selected from formula (II), namely,2-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone.

Another preferred subgroup of compounds is that subgroup wherein A is--O--; Z¹ and Z² are both --O--; R¹ and R⁴ are each independentlyhydrogen or --OR⁸ ; R² is --C(NH)NH₂ ; R³ is --C(O)N(R⁸)R⁹,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); R⁵ is hydrogen,alkyl, aryl (optionally substituted by halo), or aralkyl (optionallysubstituted halo); R⁶ is hydrogen, alkyl, --R¹⁰ --C(O)OR⁸, --R¹⁰--C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --R¹⁰ --N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹,--R¹⁰ OR⁸, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --SR⁸, or --R¹⁰ --S(O)₂ R¹¹ ; orR⁶ is aralkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl, haloalkoxyand --OR⁸); or R⁶ is imidazolylalkyl or indolylalkyl; R⁷ is hydrogen oralkyl; each R⁸ and R⁹ is independently hydrogen, alkyl, aryl, oraralkyl; R¹⁰ is a straight or branched alkylene chain; and R¹¹ is alkylor aryl.

Of this subgroup of compounds, a preferred class of compounds is thatclass wherein R¹ is --OR⁸ ; R² is --C(NH)NH₂ ; R³ is --C(O)N(R⁸)R⁹,(1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl); R⁵ is hydrogen,alkyl, aryl or aralkyl; R⁶ is hydrogen, alkyl, --R¹⁰ --C(O)OR⁸, --R¹⁰--C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --R¹⁰ --N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹,--R¹⁰ OR⁸, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --SR⁸, or --R¹⁰ --S(O)₂ R¹¹ ; orR⁶ is aralkyl (optionally substituted by one or more substituentsselected from the group consisting of methyl and hydroxy); or R⁶ isimidazolylalkyl or indolylalkyl; R⁷ is hydrogen or alkyl; each R⁸ and R⁹is independently hydrogen, alkyl, aryl, or aralkyl; R¹⁰ is a straight orbranched alkylene chain; and R¹¹ is alkyl or aryl.

Of this class of compounds, a preferred subclass of compounds is thatsubclass wherein A is --O--; Z¹ and Z² are both --O--; R¹ is hydroxy; R²is --C(NH)NH₂ ; R³ is --C(O)N(CH₃)₂ ; and R⁴, R⁵, R⁶, and R⁷ arehydrogen.

A preferred compound of this subclass of compounds is that compoundselected from formula (I), namely,2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one.

Preparation of Compounds of The Invention

It is understood that in the following description, combinations ofsubstituents and/or variables (e.g., R⁶ and R⁷) in the depictedcompounds are permissible only if such combinations result in stablecompounds.

A. Preparation of Compounds of Formula Ia)

Compounds of formula (Ia) are compounds of formula (I) where A is--N(H)--, Z¹ and Z² are both --O-- and R² is --C(NH)NH₂. These compoundsmay be prepared as illustrated in the following Reaction Scheme 1wherein R¹ and R⁴ are each independently hydrogen, halo, alkyl, --OR⁸,--C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, or --N(R⁸)C(O)R⁹, or --N(H)S(O)₂R¹¹ ; R³ is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido,guanidino, --OR⁸, --C(NH)NH₂, --C(NH)N(H)OR⁸, --C(O)N(R⁸)R⁹, --R¹⁰--C(O)N(R⁸)R⁹, --CH(OH)C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --R¹⁰ --N(R⁸)R⁹,--C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --N(R⁸)C(O)R⁸, (1,2)-tetrahydropyrimidinyl(optionally substituted by alkyl), (1,2)-imidazolyl (optionallysubstituted by alkyl), or (1,2)-imidazolinyl (optionally substituted byalkyl); R⁵ is hydrogen, alkyl, aryl (optionally substituted by halo,alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino,carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R⁶ is hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl,--C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --C(O)--R¹⁰ --N(R⁸)R⁹,--R¹⁰ --C(O)R⁸, --R¹⁰ --C(O)N(R⁸)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(OR⁹)--R¹⁰--N(R⁸)(R⁹), --C(R⁸)(OR⁸)C(O)OR⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂,--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --C(R⁸)(OR⁸)R⁹,--R¹⁰ --N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(O)OR¹¹, --R¹⁰ --N(R⁸)C(O)R⁹, --R¹⁰--N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)S(O)₂ R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹,--R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)N(R⁸)R⁹, --R¹⁰--N(R⁸)--R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --N(R⁸)S(O)R⁹, --R¹⁰ OR⁸,--R¹⁰ --ON(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ --OS(O)₂ OR⁸, --R¹⁰ --P(O)(OR⁸)R⁹,--R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --P(O)(OR⁸)₂, --R¹⁰ --SR⁸, --R¹⁰ --S--R¹⁰--C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)R⁹, --R¹⁰ --S--R¹⁰--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)C(O)OR⁸, --R¹⁰ --S--R¹⁰--N(R⁸)C(O)R⁸, --R¹⁰ --S--S--R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰--SC(O)N(R⁸)R⁹, --R¹⁰ --SC(S)N(R⁸)R⁹, --R¹⁰ --S(O)R⁸, --R¹⁰ --S(O)₂ R¹¹,--R¹⁰ --S(O)OR⁸, --R¹⁰ --S(O)₂ OR⁸, --R¹⁰ --S(O)₂ N(R⁸)R⁹, --R¹⁰--S(O)(NR⁸)R⁹ ; or R⁶ is aryl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy, --OR⁸, --SR⁸, --N(R⁸)R⁹, --C(O)OR⁸,--C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is aralkyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, haloalkoxy, --OR⁸, --SR⁸,--N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); orR⁶ is heterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl,haloalkoxy, aralkyl, --OR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy, aralkyl, --OR⁸, --SR⁸, --C(O)OR⁸, --N(R⁸)R⁹,--C(O)N(R⁸)R⁹), --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is adamantyl(optionally substituted by alkyl, halo, haloalkyl, haloalkoxy, --OR⁸,--SR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and--OP(O)(OR⁸)₂); or R⁶ is adamantylalkyl (where the adamantyl radical isoptionally substituted by alkyl, halo, haloalkyl, haloalkoxy, --OR⁸,--SR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and--OP(O)(OR⁸)₂); R⁷ is hydrogen, alkyl, cycloalkyl, or aryl; each R⁸ andR⁹ is independently hydrogen, alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹⁰ is a straight orbranched alkylene chain; R¹¹ is alkyl, aryl (optionally substituted byhalo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹² is hydrogen,alkyl, aryl or aralkyl; and X is halo: ##STR3##

Compounds of formulae (A), (B), (D), and (G) are commercially available,for example, from Aldrich Chemical Co., or Sigma Chemical Co., or ICNBiomedicals, or may be prepared according to methods known to thoseskilled in the art.

In general, compounds of formula (Ia) were prepared by first treating acompound of formula (A) in an aprotic solvent, for example,acetonitrile, at temperatures from about -10° C. to about 10° C.,preferably at about 0° C., in the presence of a base, preferably cesiumcarbonate, with an equimolar amount of a compound of formula (B). Theresulting reaction mixture was stirred at ambient temperature for about12 to about 16 hours, preferably for about 16 hours. A compound offormula (C) was then isolated from the reaction mixture by standardisolation techniques, such as in vacuo removal of solvent andchromatography.

The compound of formula (C) in an aprotic solvent, preferablyacetonitrile, at temperatures from about -10° C. to about 10° C.,preferably at about ° C., was treated with an equimolar amount of acompound of formula (D) in the presence of a base, preferably cesiumcarbonate. The resulting mixture was allowed to warm to ambienttemperature and stirred for about 1 hour to about 4 hours, preferablyfor about 2 hours. A compound of formula (E) was then isolated from thereaction mixture by standard isolation techniques, such as evaporationof the solvents.

The compound of formula (E) in a protic solvent, preferably a loweralkanol such as methanol, at temperatures from about -10° C. to about10° C., preferably at about 0° C., was then treated with a strongoxidizing agent, such as potassium metabisulfite (KHSO₅) in water. Theresulting reaction mixture was stirred for about 12 hours to about 16hours, preferably for about 15 hours, at ambient temperature. Thereaction mixture is then concentrated and extracted with an aproticorganic solvent, such as methylene chloride. A compound of formula (F)was isolated from the organic layer by standard isolation techniques,such as evaporation of the solvents.

The compound of formula (F) in an aprotic solvent, preferablyacetonitrile, at temperatures from about -10° C. to about 10° C.,preferably at about 0° C., was treated with an equimolar amount of acompound of formula (G) in the presence of a base, preferably cesiumcarbonate. The resulting reaction mixture was stirred for 15 minutes toabout 1 hour, preferably for about 15 minutes. A compound of formula (H)was isolated from the reaction mixture by standard isolation techniques,such as evaporation of the solvents and chromatography.

The compound of formula (H) in a mixture of a water miscible etherealsolvent, such as tetrahydrofuran, and an aqueous weak mineral acid, suchas 10% hydrochloric acid, was treated with a reducing agent, such asgranular zinc or hydrogen/palladium on carbon. The reaction mixture washeated for about 10 minutes to about 1 hour, preferably for about 30minutes, at about 50° C. to about 100° C., preferably at about 70° C.The volatiles were evaporated and the resulting acidic solution wasneutralized by a weak base, such as sodium bicarbonate. The compound offormula (J) was then isolated from the reaction mixture by standardisolation techniques, such as extraction with an organic solvent andevaporation of the solvent.

The compound of formula (J) was then dissolved in a lower alkanol,preferably ethanol, at temperatures from about -10° C. to about 10° C.,preferably at about 0° C., and the resulting solution was then saturatedwith a mineral acid gas, preferably hydrochloric acid. The reactionmixture was sealed and allowed to warm to ambient temperature over aperiod of time from about 12 hours to about 16 hours, preferably forabout 16 hours. The reaction mixture was concentrated and a polarsolvent, such as ether, was added to the concentrated mixture. Theresulting precipitate was then dissolved in a lower alkanol, preferablyethanol, and the resulting solution was cooled to about -10° C. to about10° C., preferably to about 0° C., and then treated with anhydrousammonia (gas) for about 5 minutes to about 20 minutes, preferably forabout 10 minutes. The reaction mixture was sealed and heated totemperatures from about ambient temperature to about 100° C., preferablyto about 60° C., for about I hour to about 2 hours, preferably for about2 hours. The reaction mixture was cooled and the solvents wereevaporated. A compound of formula (Ia) was isolated from the reactionmixture by standard isolation techniques, such as filtration,evaporation of the solvents, and purification by preparative HPLC.

The compounds of formula (Ia) so formed may further be treated by themethod described in Marfat, A., et al., Synthesis (1987), Vol. 5, p.515, with a compound of formula XR⁵ where X is bromo or chloro and R⁵ isalkyl or optionally substituted aralkyl as described above in theSummary of the Invention to prepare compounds of formula (Ia) whereinthe nitrogen atom at the 5-position is substituted by alkyl oroptionally substituted aralkyl.

Alternatively, the compounds of formula (Ia) may further be treated withan ortho-nitrohaloaromatic, preferably with anortho-nitro-fluoroaromatic, such as ortho-nitrofluorobenzene, in thepresence of a strong base, such as sodium hydride, to produce compoundsof formula (Ia) wherein the nitrogen at the 5-position is substituted bya nitro-aryl group, such as 2-nitrophenyl. Reductive de-amination of thenitro-aryl group can then be carried out by first reducing the nitrogroup to the corresponding amino group by treating the compound withSnCl₂ as described in Bellamy, F. D., et al., Tetrahedron Letters(1984), Vol. 26, p. 839. The resulting amino compound can then bede-aminated by treating the compound with a standard deaminating agent,such as t-butylnitrite, in an aprotic solvent, such as DMF, attemperature from about 35° C. to about 90° C., preferably at about 65°C. (see Doyle, M. P., et al., J. Org. Chem. (1974), Vol. 42, p. 3494).

Alternatively, instead of treating the resulting solution above withanhydrous ammonia, the resulting solution may be treated with a compoundof the formula NH₂ OR⁸ to afford the compound of formula (I) wherein R²is --C(NH)N(H)OR⁸.

Compounds of formula (Ia) wherein R³ is --C(NH)NH₂ or --C(NH)N(H)OR⁸ areproduced from the corresponding cyano compounds in a similar manner asthat described above for compounds of formula (J).

In addition, compounds of formula (Ia) wherein R¹, R³, R⁴, R⁵ or R⁶contains a --C(O)N(R⁸)R⁹ group or a --C(O)OR⁸ group (where each R⁸ andR⁹ is independently alkyl, optionally substituted aryl or optionallysubstituted aralkyl) may be hydrolyzed under acidic conditions toprepare compounds of the invention where R¹, R³, R⁴, R⁵ or R⁶ contains acarboxy group.

In addition, compounds of formula (Ia) where R¹, R³, R⁴, R⁵ or R⁶contains an amino group can be treated with the appropriate alkylatingagents to afford the corresponding compounds of formula (Ia) where R¹,R³, R⁴, R⁵ or R⁶ contains --N(R⁸)R⁹ or --N(R⁸)C(O)R⁹ where each R⁸ andR⁹ is independently hydrogen, alkyl, optionally substituted aryl oroptionally substituted aralkyl.

In addition, compounds of formula (Ia) wherein R¹, R³, R⁴, R⁵ or R⁶contains a --C(O)OR⁸ group where R⁸ is hydrogen, alkyl, optionallysubstituted aryl or optionally substituted aralkyl may be amidated understandard amidation conditions to form the corresponding compounds offormula (Ia) where R¹, R³, R⁴, R⁵ or R⁶ contains a --C(O)N(R⁸)R⁹ groupwhere R⁸ and R⁹ are independently hydrogen, alkyl, optionallysubstituted aryl or optionally substituted aralkyl.

Compounds of formula (Ia) may be further treated with the appropriateacid halide, preferably acid chloride, or with the appropriate acidanhydride or an equivalent, to yield compounds of the invention whereinR² is --C(NH)N(H)C(O)R⁸ where R⁸ is hydrogen, alkyl, optionallysubstituted aryl or optionally substituted aralkyl. Alternatively,compounds of formula (Ia) may further be treated with carbamoylchlorides or their equivalents to yield compounds of the invention whereR² is --C(NH)N(H)C(O)OR¹¹ where R¹¹ is described above in the Summary ofthe Invention.

Alternatively, compounds of formula (Ia) may be further treated withcompounds of the formula R¹¹ --S(O)₂ -imidazole, where R¹¹ is asdescribed in the Summary of the Invention, in a polar solvent, such asmethylene chloride, at ambient temperature to afford compounds of theinvention where R² is --C(NH)N(H)S(O)₂ ^(R11).

Alternatively, compounds of formula (Ia) may be further treated with anappropriately N--R⁸ -substituted phenylcarbamate in a polar solvent,preferably methylene chloride, at ambient temperature, for about 6 to 24hours, preferably for about 12 hours, to afford compounds of theinvention where R² is --C(NH)N(H)C(O)N(H)R⁸.

B. Preparation of Compounds of Formula (IIa)

Compounds of formula (IIa) are compounds of formula (II) wherein A is--N(H)--; Z¹ and Z² are both --O--; and R² is --C(NH)NH₂. Thesecompounds may be prepared as illustrated in the following ReactionScheme 2 wherein R¹, R³, R⁴, R⁵, R⁶, R⁷ and R¹² are as defined ReactionScheme 1; and X is halo: ##STR4##

Compounds of formulae (A), (B), (D) and (G) are commercially available,for example, from Aldrich Chemical Co., or Sigma Chemical Co., or ICNBiomedicals, or may be prepared according to methods known to thoseskilled in the art.

In general, compounds of formula (IIa) were prepared by first treating acompound of formula (A) with a compound of formula (G) in a mannersimilar to that described above for the preparation of compounds offormula (H) from compounds of formula (F) and (G). The resultingcompound of formula (K) was isolated from the reaction mixture andtreated with a compound of formula (D) in a manner similar to thatdescribed above for the compound of formula (C). The resulting compoundof formula (L) was isolated from the reaction mixture and then oxidizedin a manner similar to that described above for the compounds of formula(E). The resulting compound of formula (M) was isolated from thereaction mixture and then treated with a compound of formula (B) in amanner similar to that described above for the compound of formula (A).The resulting compound of formula (N) was isolated from the reactionmixture, and then was reduced and cyclized in a manner similar to thatdescribed above for a compound of formula (H). The resulting compound offormula (O) was then treated in a manner similar to that described abovefor the compound of formula (J). The resulting compound of formula (IIa)was isolated from the reaction mixture by standard technique.

In addition, all the various substituent conversions described above forthe compounds of formula (Ia) apply to the compounds of formula (IIa) toafford additional compounds of the invention not specifically depictedin the foregoing Reaction Scheme.

C. Preparation of Compounds of formula (Ib)

Compounds of formula (Ib) are compounds of formula (I) wherein A is--O--; Z¹ and Z² are both --O--; and R² is --C(NH)NH₂. These compoundsmay be prepared as illustrated below in Reaction Scheme 3 wherein R¹,R³, R⁴, R⁵, R⁶, R⁷ and R¹² are as described above for Scheme 1; and X ishalo: ##STR5##

Compounds of formula (C) are prepared as described above in ReactionScheme 1. Compounds of formula (P) and formula (G) are commerciallyavailable, for example, from Aldrich Chemical Co. or Sigma Chemical Co,or may be prepared according to methods known to those skilled in theart.

In general, the compounds of formula (Ib) were prepared by firstgenerating the alkoxide ion of the compound of formula (P) by treatingthe compound with a strong base, preferably sodium hydride, in a polaraprotic solvent, preferably tetrahydrofuran, from about 0° C. to aboutambient temperature, preferably at about 0° C. The resulting solution,containing the alkoxide was added dropwise to a compound of formula (C)at about 0° C. to about 10° C., preferably at about 0° C. the reactionmixture was stirred for about 30 minutes to about 2 hours, preferablyfor about 1 hour, from about 0° C. to about 10° C., preferably at about0° C. The reaction mixture was then warmed to ambient temperature andstirred for about 1 hour to about 3 hours, preferably for about 2 hours.The compound of formula (Q) was then isolated from the reaction mixtureby conventional isolation techniques, such as by evaporation of thevolatiles.

The compound of formula (Q) was then oxidized to a compound of formula(R) in a manner similar to that described above for compounds of formula(E) in preparing compounds of formula (F). The compound of formula (R)so formed was then treated with a compound of formula (G) to produce acompound of formula (S) in a manner similar to that described above forcompounds of formula (F) in preparing compounds of formula (H). Thecompound of formula (S) so formed was then cyclized to produce acompound of formula (T) in a manner similar to that described above forcompounds of formula (H) in preparing compounds of formula (J). Thecompound of formula (T) so formed was then treated in a manner similarto that described above for compounds of formula (J) in preparingcompounds of formula (Ia). to produce a compound of formula (Ib).

In addition, all the various substituent conversions described above forthe compounds of formula (Ia) apply to the compounds of formula (Ib) soformed to afford additional compounds of the invention not specificallydepicted in the foregoing Reaction Scheme.

D. Preparation of Compounds of Formula (IIb)

Compounds of formula (llb) are compounds of formula (II) wherein A is--O--; Z¹ and Z² are both --O--; and R² is --C(NH)NH₂. These compoundsmay be prepared as illustrated below in Reaction Scheme 3 wherein R¹,R³, R⁴, R⁵, R⁶, R⁷ and R¹² are as described above for Reaction Scheme 1;and X is halo: ##STR6##

Compounds of formula (K) are prepared as described above in ReactionScheme 2. Compounds of formula (P) and formula (B) are commerciallyavailable, for example, from Aldrich Chemical Co. or Sigma Chemical Co,or may be prepared according to methods known to those skilled in theart.

In general, the compounds of formula (IIb) are prepared by firstgenerating the alkoxide ion of the compound of formula (P) as describedabove for compounds of formula (C) in Reaction Scheme and then treatinga compound of formula (K) with the alkoxide so formed to produce acompound of formula (U). The compound of formula (U) is then oxidized toa compound of formula (V) in a manner similar to that described abovefor compounds of formula (L) in preparing compounds of formula (M). Thecompound of formula (V) so formed was then treated with a compound offormula (B) to produce a compound of formula (W) in a mariner similar tothat described above for compounds of formula (M) in preparing compoundsof formula (N). The compound of formula (W) so formed was then cyclizedto produce a compound of formula (X) in a manner similar to thatdescribed above for compounds of formula (N) in preparing compounds offormula (O). The compound of formula (X) so formed was then treated in amanner similar to that described above for compounds of formula (O) inpreparing compounds of formula (IIa) to produce a compound of formula(IIb).

In addition, all the various substituent conversions described above forthe compounds of formula (Ia) apply to the compounds of formula (IIb) soformed to afford additional compounds of the invention not specificallydepicted in the foregoing Reaction Scheme.

In addition, all compounds of the invention that exist in free base formor free acid form may be converted to their pharmaceutically acceptablesalts by treatment with the appropriate inorganic or organic acid, or bythe appropriate inorganic or organic base. Salts of the compounds of theinvention can also be converted to the free base form or to the freeacid form or to another salt by methods known to those of ordinary skillin the chemical arts.

The following specific preparations and examples are provided as a guideto assist in the practice of the invention, and are not intended as alimitation on the scope of the invention.

PREPARATION 1 Compounds of formula (C), formula (N) and formula (W)

A. To 2-methylthio-4,6-dichloro-5-nitropyrimidine, a compound of formula(A), (5.0 g, 20.8 mmol) in 200 mL acetonitrile at 0° C. was added cesiumcarbonate (8.82 g, 27.1 mmol) followed by the addition of3-(dimethylaminocarbonyl)phenol (3.44 g, 20.8 mmol), a compound offormula (B), and the reaction mixture was stirred for 16 hours. Thevolatiles were evaporated and the residue chromatographed on silica gel(CH₂ Cl₂ /ethyl acetate, 7:12) to afford 6.3 g (83% yield) of2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine,a compound of formula (C).

B. In a similar manner, the following compounds of formula (C) are made:

2-methylthio-4-chloro-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-methyl-3-(dimethylaminocarbonyl)phenyoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)-phenoxy)pyrimidine;and

2-methylthio-4-chloro-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine.

C. In a similar manner,2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (M), prepared as described below in Preparation 4,is treated with 3-(dimethylaminocarbonyl)phenol, a compound of formula(B) to afford2-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (N).

D. In a similar manner, the following compounds of formula (N) are made:

2-(3-methylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-(3-chloro-5-methoxyphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-(4-trifluoromethylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-(3,5-dinitrophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-(3-guanidino-5-methylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-(3-ureidophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-(3-(2-chloroethyl)-5-methylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-(4-ethoxycarbonylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazol-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-(3-t-butoxycarbonylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-amino-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-amino-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-amino-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-amino-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-amino-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxyethyl)amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-methylpropyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-3-methylbutyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-methylbutyl)amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-phenylethyl)amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-(4-mercaptophenyl)ethyl)amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-3-(methylthio)propyl)amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-(imidazol-4-yl)ethyl)amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-hydroxyethyl)amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-hydroxypropyl)amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-(aminocarbonyl)ethyl)amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-3-(aminocarbonyl)propyl)amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1,2-dicarboxyethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

-(3-guanidinophenoxy)-4-(1,3-dicarboxypropyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-5-aminopentyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;and

2-(3-guanidinophenoxy)-4-(1-carboxy-4-guanidinobutyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine.

E. In a similar manner,2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (V), is treated with3-(dimethylaminocarbonyl)phenol, a compound of formula (B), to afford2-(3-dimethyl-aminocarbonylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-benzyloxy-5-cyano-phenoxy)pyrimidine,a compound of formula (W).

F. In a similar manner, the following compounds of formula (W) areprepared:

2-(3-methylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-(3-chloro-5-methoxyphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-(4-trifluoromethylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-(3,5-dinitrophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-(3-guanidino-5-methylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-(3-ureidophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-(3-(2-chloroethyl)-5-methylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-(4-ethoxycarbonylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazol-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-(3-t-butoxycarbonylphenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxyethoxy)-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-methylpropoxy)-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-3-methylbutoxy)-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-methylbutoxy)-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-phenylethoxy)-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-(3-dimethylaminocarbonylphenoxy)-4-(1-carboxy-2-(4-mercaptophenyl)ethoxy)-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-3-(methylthio)propoxy)-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-(imidazol-4-yl)ethoxy)-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-hydroxyethoxy)-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-hydroxypropoxy)-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-2-(aminocarbonyl)ethoxy)-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-3-(aminocarbonyl)propoxy)-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1,2-dicarboxyethoxy)-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1,3-dicarboxypropoxy)-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-(3-guanidinophenoxy)-4-(1-carboxy-5-aminopentoxy)-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;and

2-(3-guanidinophenoxy)-4-(1-carboxy-4-guanidinobutoxy)-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine.

PREPARATION 2 Compounds of formula (E) and formula (L)

A. To2-methylthio-4-chloro-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine,a compound of formula (C), (3.0 g 8.14 mmol) in 80 mL of acetonitrile at0° C. was added glycine ethyl ester hydrochloride, a compound of formula(D), (1.14 g, 8.14 mmol), followed by the addition of cesium carbonate(6.1 g, 18.7 mmol). The reaction mixture was allowed to warm to ambienttemperature and then stirred for 2 hours. The volatiles were evaporatedto yield 3.6 g of2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)-phenoxypyrimidine,a compound of formula (E).

B. In a similar manner, the following compounds of formula (E) areprepared:

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(diethylaminocarbonyl)-phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxyethyl)amino-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylpropyl)amino-5-nitro-6-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-methylbutyl)amino-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylbutyl)amino-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-phenylethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(4-mercaptophenyl)ethyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(methylthio)propyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-mercaptoethyl)amino-5-nitro-6-(5-dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(indolin-3-yl)ethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(imidazol-4-yl)ethyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxyethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxypropyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(aminocarbonyl)ethyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(aminocarbonyl)propyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)-methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1,2-dicarboxyethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1,3-dicarboxypropyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-5-aminopentyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;and

2-methylthio-4-(1-carboxy-4-guanidinobutyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine.

C. In a similar manner,2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (K), is treated with glycine ethyl esterhydrochloride, a compound of formula (D), to yield2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (L).

D. In a similar manner, the following compounds of formula (L) areprepared:

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxyethyl)amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylpropyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-methylbutyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylbutyl)amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-phenylethyl)amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(4-mercaptophenyl)ethyl)amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(methylthio)propyl)amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(imidazol-4-yl)ethyl)amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxyethyl)amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxypropyl)amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(aminocarbonyl)ethyl)amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(aminocarbonyl)propyl)amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1,2-dicarboxyethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1,3-dicarboxypropyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-5-aminopentyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;and

2-methylthio-4-(1-carboxy-4-guanidinobutyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine.

PREPARATION 3 Compounds of formula (Q) and (U)

A. To sodium hydride (0.63 g, 15.72 mmol) in 30 mL tetrahydrofuran at 0°C. was added ethyl glycolate (1.15 mL, 12.09 mmol) over 10 minutes. Theresulting alkoxide was then added to2-methylthio-4-chloro-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine,a compound of formula (C), (4.46 g., 12.09 mmol), dropwise at 0° C. over5 minutes. After 1 hours, the reaction mixture was warmed to ambienttemperature and stirred for an additional 2 hours. The volatiles wereevaporated to yield 2.55 g (48% yield) of2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine,a compound of formula (Q), as a yellow oil.

B. In a similar manner, the following compounds of formula (Q) areprepared:

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidine-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxyethoxy)-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylpropoxy)-5-nitro-6-(5-methyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-methylbutoxy)-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylbutoxy)-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-phenylethoxy)-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(4-mercaptophenyl)ethoxy)-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(methylthio)propoxy)-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-mercaptoethoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(indolin-3-yl)ethoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(imidazol-4-yl)ethoxy)-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxyethoxy)-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxypropoxy)-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(aminocarbonyl)ethoxy)-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(aminocarbonyl)propoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1,2-dicarboxyethoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylthio-4-(1,3-dicarboxypropoxy)-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-5-aminopentoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;and

2-methylthio-4-(1-carboxy-4-guanidinobutoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine.

C. In a similar manner,2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (K), is treated with ethyl glycolate, a compoundof formula (P), to yield2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (U).

D. In a similar manner, the following compounds of formula (U) areprepared:

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonylmethoxy-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxyethoxy)-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylpropoxy)-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-methylbutoxy)-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-methylbutoxy)-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-phenylethoxy)-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(4-mercaptophenyl)ethoxy)-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(methylthio)propoxy)-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(imidazol-4-yl)ethoxy)-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxyethoxy)-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-hydroxypropoxy)-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-2-(aminocarbonyl)ethoxy)-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-3-(aminocarbonyl)propoxy)-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1,2-dicarboxyethoxy)-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-(1,3-dicarboxypropoxy)-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-(1-carboxy-5-aminopentoxy)-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;and

2-methylthio-4-(1-carboxy-4-guanidinobutoxy)-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine.

PREPARATION 4 Compounds of formula (F), formula (M), formula (R) andFormula (V)

A. To2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxypyrimidine,a compound of formula (E), 3.54 g, 8.14 mmol) in 40 mL methanol at 0° C.was added potassium metabisulfite (7.5 g, 24.4. mmol) in 40 mL water.The resulting suspension was allowed to warm to ambient temperature andstirred for 15 hours. The reaction mixture was concentrated to about 25mL and extracted with methylene chloride (200 mL). The organic layer wasdried (Na₂ SO₄) and evaporated to afford 3.5 g of2-methylsulfonyl-4-(ethoxycarbonylmethyl)methyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxypyrimidine,a compound of formula (F), as a white solid.

B. In a similar manner, the following compounds of formula (F) areprepared:

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(diethylamino-carbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethylamino-5-nitro-6-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidine-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxyethyl)amino-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-methylpropyl)amino-5-nitro-6-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-methylbutyl)amino-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-methylbutyl)amino-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-phenylethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(4-sulfonylphenyl)ethyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(methylsulfonyl)propyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-sulfonylethyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(indolin-3-yl)ethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(imidazol-4-yl)ethyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxyethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxypropyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(aminocarbonyl)ethyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(aminocarbonyl)propyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1,2-dicarboxyethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1,3-dicarboxypropyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-5-aminopentyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;and

2-methylsulfonyl-4-(1-carboxy-4-guanidinobutyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine.

C. In a similar manner,2-methylthio-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (L), was oxidized to afford2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (M).

D. In a similar manner, the following compounds of formula (M) areprepared:

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxyethyl)amino-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-methylpropyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-methylbutyl)amino-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-methylbutyl)amino-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-phenylethyl)amino-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(4-sulfonylphenyl)ethyl)amino-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(methylsulfonyl)propyl)amino-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(imidazol-4-yl)ethyl)amino-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxyethyl)amino-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxypropyl)amino-5-nitro-6-13-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(aminocarbonyl)ethyl)amino-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(aminocarbonyl)propyl)amino-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

-methylsulfonyl-4-(1,2-dicarboxyethyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1,3-dicarboxypropyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-5-aminopentyl)amino-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;and

2-methylsulfonyl-4-(1-carboxy-4-guanidinobutyl)amino-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine.

E. In a similar manner,2-methylthio-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine,a compound of formula (Q), was oxidized to afford2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine,a compound of formula (R).

F. In a similar manner, the following compounds of formula (R) areprepared:

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxyethoxy)-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

-methylsulfonyl-4-(1-carboxy-2-methylpropoxy)-5-nitro-6-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-methylbutoxy)-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-methylbutoxy)-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-phenylethoxy)-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(4-sulfonylphenyl)ethoxy)-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(methylsulfonyl)propoxy)-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-sulfonylethoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(indolin-3-yl)ethoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(imidazol-4-yl)ethoxy)-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxyethoxy)-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxypropoxy)-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(aminocarbonyl)ethoxy)-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(aminocarbonyl)propoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1,2-dicarboxyethoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1,3-dicarboxypropoxy)-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-5-aminopentoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;and

2-methylsulfonyl-4-(1-carboxy-4-guanidinobutoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine.

G. In a similar manner,2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (U), is oxidized to afford2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (V).

H. In a similar manner, the following compounds of formula (V) areprepared:

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxyethoxy)-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-methylpropoxy)-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-methylbutoxy)-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-methylbutoxy)-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-phenylethoxy)-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(4-sulfonylphenyl)ethoxy)-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(methylsulfonyl)propoxy)-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(imidazol-4-yl)ethoxy)-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxyethoxy)-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-hydroxypropoxy)-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-2-(aminocarbonyl)ethoxy)-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-3-(aminocarbonyl)propoxy)-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1,2-dicarboxyethoxy)-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1,3-dicarboxypropoxy)-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylsulfonyl-4-(1-carboxy-5-aminopentoxy)-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;and

2-methylsulfonyl-4-(1-carboxy-4-guanidinobutoxy)-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine.

PREPARATION 5 Compounds of formula (H), formula (K) and formula (S)

A. To2-methylsulfonyl-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxypyrimidine(3.5 g, 7.49 mmol), a compound of formula (F), in 80 mL acetonitrile at0° C. was added cesium carbonate (3.17 g, 9.73 mmol), followed by theaddition of 2-benzyloxy-5-cyanophenol (1.6 g, 7.49 mmol). The resultingreaction mixture was stirred for 15 minutes. The volatiles wereevaporated and the residue chromatographed on silica (CH₂ Cl₂ /ethylacetate, 10:1, then 5:1) to afford 2.1 g (46% yield) of2-(2-benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)-phenoxypyrimidine,a compound of formula (H).

B. In a similar manner, the following compounds of formula (H) areprepared:

2-(2-benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(diethylamino-carbonyl)pyrimidine;

2-(2-methoxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-methyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-ethoxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-phenoxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-chloro-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-methyl-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-(2-t-butyl-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-(2-nitro-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-(2-carboxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-(2-diethylaminocarbonyl-5-cyanophenoxy)-4-(1-carboxyethyl)amino-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-amino-5-cyanophenoxy)-4-(1-carboxy-2-methylpropyl)amino-5-nitro-6-(5-methyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1-carboxy-3-methylbutyl)amino-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-methoxy-5-cyanophenoxy)-4-(1-carboxy-2-methylbutyl)amino-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-ethoxy-5-cyanophenoxy)-4-(1-carboxy-2-phenylethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-phenoxy-5-cyanophenoxy)-4-(1-carboxy-2-(4-sulfonylphenyl)ethyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-(2-chloro-5-cyanophenoxy)-4-(1-carboxy-3-()propyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-(2-methyl-5-cyanophenoxy)-4-(1-carboxy-2-sulfonylethyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-(2-t-butyl-5-cyanophenoxy)-4-(1-carboxy-2-(indolin-3-yl)ethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-nitro-5-cyanophenoxy)-4-(1-carboxy-2-(imidazol-4-yl)ethyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-(2-carboxy-5-cyanophenoxy)-4-(1-carboxy-2-hydroxyethyl)amino-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-4-(1-carboxy-2-hydroxypropyl)amino-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-(2-diethylaminocarbonyl-5-cyanophenoxy)-4-(1-carboxy-2-(aminocarbonyl)ethyl)amino-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-(2-amino-5-cyanophenoxy)-4-(1-carboxy-3-(aminocarbonyl)propyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1,2-dicarboxyethyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1,3-dicarboxypropyl)amino-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1-carboxy-5-aminopentyl)amino-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-(3-(imidazol-2-yl)phenoxy)pyrimidine;and

2-(2-benzyloxy-5-cyanophenoxy)-4-(1-carboxy-4-guanidinobutyl)amino-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine.

C. In a similar manner, 2-methylthio-4,6-dichloro-5-nitropyrimidine, acompound of formula (A), was treated with 2-benzyloxy-5-cyanophenol toyield2-methylthio-4-chloro-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (K).

D. In a similar manner, the following compounds of formula (K) areprepared:

2-methylthio-4-chloro-5-nitro-6-(2-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-methoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-ethoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-phenoxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-chloro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-bromo-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-methyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-methyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-nitro-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-nitro-4-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-carboxy-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-carboxy-4-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-t-butoxycarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-t-butoxycarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-aminocarbonyl-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-aminocarbonyl-4-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine;

2-methylthio-4-chloro-5-nitro-6-(2-dimethylamino-5-cyanophenoxy)pyrimidine;and

2-methylthio-4-chloro-5-nitro-6-(3-dimethylamino-4-cyanophenoxy)pyrimidine.

E. In a similar manner,2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine,a compound of formula (R), was treated with 2-benzyloxy-5-cyanophenol toyield2-(2-benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine,a compound of formula (S).

F. In a similar manner, the following compounds of formula (S) are made:

2-(2-benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-methoxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-methyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-ethoxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-phenoxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-chloro-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-methyl-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-(2-t-butyl-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-(2-nitro-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2yl)-phenoxy)pyrimidine;

2-(2-carboxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-(2-diethylaminocarbonyl-5-cyanophenoxy)-4-(1-carboxyethoxy)-5-nitro-6-(3-(diethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-amino-5-cyanophenoxy)-4-(1-carboxy-2-methylpropoxy)-5-nitro-6-(5-methyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1-carboxy-3-methylbutoxy)-5-nitro-6-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-methoxy-5-cyanophenoxy)-4-(1-carboxy-2-methylbutoxy)-5-nitro-6-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-ethoxy-5-cyanophenoxy)-4-(1-carboxy-2-phenylethoxy)-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-phenoxy-5-cyanophenoxy)-4-(1-carboxy-2-(4-sulfonylphenyl)ethoxy)-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-(2-chloro-5-cyanophenoxy)-4-(1-carboxy-3-(methylsulfonyl)propoxy)-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-(2-methyl-5-cyanophenoxy)-4-(1-carboxy-2-sulfonylethoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-(2-t-butyl-5-cyanophenoxy)-4-(1-carboxy-2-(indolin-3-yl)ethoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-nitro-5-cyanophenoxy)-4-(1-carboxy-2-(imidazol-4-yl)ethoxy)-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-(2-carboxy-5-cyanophenoxy)-4-(1-carboxy-2-hydroxyethoxy)-5-nitro-6-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-4-(1-carboxy-2-hydroxypropoxy)-5-nitro-6-(5-ethoxycarbonyl-3-methylphenoxy)pyrimidine;

2-(2-diethylaminocarbonyl-5-cyanophenoxy)-4-(1-carboxy-2-(aminocarbonyl)ethoxy)-5-nitro-6-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)pyrimidine;

2-(2-amino-5-cyanophenoxy)-4-(1-carboxy-3-(aminocarbonyl)propoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1,2-dicarboxyethoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1,3-dicarboxypropoxy)-5-nitro-6-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)pyrimidine;

2-(2-benzyloxy-5-cyanophenoxy)-4-(1-carboxy-5-aminopentoxy)-5-nitro-6-(5-(dimethylaminocarbonyl)methyl-(3-(imidazol-2-yl)phenoxy)pyrimidine;and

2-(2-benzyloxy-5-cyanophenoxy)-4-(1-carboxy-4-guanidinobutoxy)-5-nitro-6-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)pyrimidine.

PREPARATION 6 Compounds of formula (J), formula (O), formula (T) andformula (X)

A.2-(2-Benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(3-(dimethylaminocarbonyl)phenoxy)pyrimidine(1.1 g, 1.80 mmol), a compound of formula (H), and granular zinc (0.5 g)were mixed with tetrahydrofuran (50 mL) and 10% aqueous HCl (10 mL). Thereaction mixture was heated for 30 minutes at 70° C. The volatiles wereevaporated. Saturated aqueous NaHCO₃ was added and the solutionextracted with ethyl acetate (300 mL). The organic layer was dried (Na₂SO₄) and evaporated to afford 1.35 g of2-(2-benzyloxy-5-cyanophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone,a compound of formula (J).

B. In a similar manner, the following compounds of formula (J) areprepared:

2-(2-benzyloxy-5-cyanophenoxy)-4-(3-(diethylamino-carbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-methoxy-5-cyanophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-ethoxy-5-cyanophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-phenoxy-5-cyanophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-chloro-5-cyanophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-methyl-5-cyanophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-t-butyl-5-cyanophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-cyanophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-carboxy-5-cyanophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-diethylaminocarbonyl-5-cyanophenoxy)-4-(3-(diethylaminocarbonyl)phenoxy)-7-methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-cyanophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)-7-(1-methylethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(2-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-methoxy-5-cyanophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-7-(1-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-ethoxy-5-cyanophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-7-benzyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-phenoxy-5-cyanophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-(4-sulfonylphenyl)-methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-chloro-5-cyanophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-7-(2-methylsulfonyl)ethyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-methyl-5-cyanophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-7-(sulfonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-t-butyl-5-cyanophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(indolin-3-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-cyanophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-7-(imidazol-4-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-carboxy-5-cyanophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-7-(hydroxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-5-amino-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-(1-hydroxyethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-diethylaminocarbonyl-5-cyanophenoxy)-5-amino-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-7-(aminocarbonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-cyanophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-7-(2-(aminocarbonyl)ethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(carboxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxy-5-cyanophenoxyl-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-7-(2-carboxyethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-(3-(imidazol-2-yl)phenoxyl)-7-(4-aminobutyl)-1,7-dihydro-6(5H)-pteridinone;and

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(3-guanidinopropyl)-1,7-dihydro-6(5H)-pteridinone.

C. In a similar manner,2-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonylmethyl)amino-5-nitro-6-(2-benzyloxy-5-cyanophenoxy)pyrimidine,a compound of formula (N), was reduced and cyclized to afford2-(3-dimethylaminocarbonylphenoxy)-4-(2-benzyloxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone,a compound of formula (O).

D. In a similar manner, the following compounds of formula (O) areprepared:

2-(3-methylphenoxy)-4-(2-methoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-chloro-5-methoxyphenoxy)-4-(2-ethoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(4-trifluoromethylphenoxy)-4-(3-methoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3,5-diaminophenoxy)-4-(3-ethoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidino-5-methylphenoxy)-4-(2-phenoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidino-5-methylphenoxy)-4-(2-phenoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-ureidophenoxy)-4-(3-phenoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(2-chloroethyl)-5-methylphenoxy)-4-(2-chloro-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(4-ethoxycarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminophenoxy)-4-(3-methyl-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy-4-(2-amino-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-t-butoxycarbonylphenoxy)-4-(3-amino-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-carboxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-t-butoxycarbonyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-t-butoxycarbonyl-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-aminocarbonyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-ethoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-methoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-phenoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-phenoxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-methyl-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-amino-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-amino-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-carboxy-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-carboxy-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-t-butoxycarbonyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-t-butoxycarbonyl-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-aminocarbonyl-5-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-aminocarbonyl-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-7-methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-7-(1-methylethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxyl-4-(3-bromo-5-cyanophenoxy)-7-(2-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-7-(1-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-7-benzyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-methyl-4-cyanophenoxy)-7-(4-sulfonylphenyl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxyl-4-(2-amino-5-cyanophenoxyl-7-(2-methylsulfonyl)ethyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-amino-4-cyanophenoxy)-7-(sulfonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-carboxy-5-cyanophenoxy)-7-(indolin-3-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-carboxy-4-cyanophenoxy)-7-(imidazol-4-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-t-butoxycarbonyl-5-cyanophenoxy)-7-(hydroxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-t-butoxycarbonyl-4-cyanophenoxy)-7-(1-hydroxyethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-aminocarbonyl-5-cyanophenoxy)-7-(aminocarbonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-aminocarbonyl-4-cyanophenoxy)-7-(2-(aminocarbonyl)ethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-7-(carboxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-7-(2-carboxyethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-7-(4-aminobutyl)-1,7-dihydro-6(5H)-pteridinone;and

2-(3-guanidinophenoxyl-4-(3-dimethylamino-4-cyanophenoxy)-7-(3-guanidinopropyl)-1,7-dihydro-6(5H)-pteridinone.

E. In a similar manner,2-(2-benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine,a compound of formula (S), was reduced and cyclized to afford2-(2-benzyloxy-5-cyanophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one, a compound of formula (T).

F. In a similar manner, the following compounds of formula (T) areprepared:

2-(2-benzyloxy-5-cyanophenoxy)-4-(3-(diethylamino-carbonyl)phenoxy)-5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-one;

2-(2-methoxy-5-cyanophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-ethoxy-5-cyanophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-phenoxy-5-cyanophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-chloro-5-cyanophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-methyl-5-cyanophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-t-butyl-5-cyanophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-cyanophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-carboxy-5-cyanophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-5H-pyrimido 4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-diethylaminocarbonyl-5-cyanophenoxy)-4-(3-(diethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-cyanophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)-7-methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxyl-7-(1-methylethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-methoxy-5-cyanophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-7-(2-methylpropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-ethoxy-5-cyanophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-7-(1-methylpropyl)-5H-pyrimido 4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-phenoxy-5-cyanophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-benzyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-chloro-5-cyanophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-7-(4-sulfonylphenyl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-methyl-5-cyanophenoxyl-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxyl-7-(sulfonylmethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-t-butyl-5-cyanophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(indolin-3-yl)methyl-5H-pyrimido4, 5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-cyanophenoxyl)4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-7-(imidazol-4-yl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-carboxy-5-cyanophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-7-(hydroxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxycarbonyl-5-cyanophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-(1-hydroxyethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-diethylaminocarbonyl-5-cyanophenoxyl-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxyl-7-(aminocarbonylmethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-cyanophenoxyl-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-7-(2-(aminocarbonyl)ethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxy-5-cyanophenoxyl-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxyl-7-(carboxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-7-(2-carboxyethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-(3-(imidazol-2-yl)phenoxyl-7-(4-aminobutyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one; and

2-(2-benzyloxy-5-cyanophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(3-guanidinopropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one.

G. In a similar manner,2-(3-dimethylaminocarbonylphenoxy)-4-(ethoxycarbonyl)-methoxy-5-nitro-6-(2-benzyloxy-5-cyano-phenoxy)pyrimidine,a compound of formula (W), is reduced and cyclized to afford2-(3-dimethylaminocarbonylphenoxy)-4-(2-benzyloxy-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one, a compound of formula (X).

H. In a similar manner, the following compounds of formula (X) areprepared:

2-(3-methylphenoxy)-4-(2-methoxy-5-cyanophenoxy)-5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-one;

2-(3-chloro-5-methoxyphenoxy)-4-(2-ethoxy-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(4-trifluoromethylphenoxy)-4-(3-methoxy-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3,5-diaminophenoxy)-4-(3-ethoxy-5-cyanophenoxy)-5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-one;

2-(3-guanidino-5-methylphenoxy)-4-(2-phenoxy-5-cyanophenoxyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-ureidophenoxy)-4-(3-phenoxy-5-cyanophenoxy)-5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-one;

2-(3-(2-chloroethyl)-5-methylphenoxy)-4-(2-chloro-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(4-ethoxycarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-5H-pyrimido4,5-b!1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methyl-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminophenoxy)-4-(3-methyl-4-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy-4-(2-amino-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-t-butoxycarbonylphenoxy)-4-(3-amino-4-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-carboxy-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-4-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-t-butoxycarbonyl-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-t-butoxycarbonyl-4-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-aminocarbonyl-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-4-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-7-methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-7-(1-methylethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-cyanophenoxy)-7-(2-methylpropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-7-(1-methylpropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-cyanophenoxy)-7-benzyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxyl-4-(3-methyl-4-cyanophenoxyl-7-(4-sulfonylphenyl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-amino-5-cyanophenoxyl-7-(2-methylsulfonyl)ethyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxyl-4-(3-amino-4-cyanophenoxy)-7-(sulfonylmethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-carboxy-5-cyanophenoxy)-7-(indolin-3-yl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-carboxy-4-cyanophenoxy)-7-(imidazol-4-yl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-t-butoxycarbonyl-5-cyanophenoxy)-7-(hydroxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-t-butoxycarbonyl-4-cyanophenoxy)-7-(1-hydroxyethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-aminocarbonyl-5-cyanophenoxy)-7-(aminocarbonylmethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-aminocarbonyl-4-cyanophenoxyl-7-(2-(aminocarbonyl)ethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-7-(carboxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-cyanophenoxy)-7-(2-carboxyethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-cyanophenoxy)-7-(4-aminobutyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one; and

2-(3-guanidinophenoxyl-4-(3-dimethylamino-4-cyanophenoxyl)-7-(3-guanidinopropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one.

EXAMPLE 1 Compounds of formula (Ia), formula (IIa), formula (Ib) andformula (IIb)

A.2-(2-Benzyloxy-5-cyanophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone(1.35 g, 2.52 mmol), a compound of formula (J), was dissolved in ethanol(60 mL) in a pressure vessel at 0° C. and saturated with HCl gas. Thereaction was sealed and allowed to warm to ambient temperature over 16hours. The reaction mixture was then concentrated to about 20 mL andether added to precipitate the ethyl imidate. The imidate was dissolvedin ethanol (30 mL), cooled to 0° C., and ammonia gas bubbled through thesolution for 10 minutes. The reaction was sealed and heated at 60° C.for 2 hours. The reaction was allowed to cool, the tube opened withcaution and the volatiles evaporated to afford 1.0 g of a brown residue.The residue (300 mg) was hydrogenated in ethanol over 10% Pd/C followedby addition of 6N HCl (8.0 mL) and heating to 100° C. The reaction wasfiltered and the filtrate evaporated to afford 120 mg of the crudeproduct. Purification by preparative HPLC afforded 60 mg of2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone,a compound of formula (Ia), NMR (DMSO-d₆) 10.30 (brs,1), 9.00 (brs,2),8.80 (brs,2), 8.00 (br,1), 7.60 (m,2), 7.60 (dd, 1), 7.20-730 (m,4),7.00 (d,1), 4.00 (s,2), 2.90 (s,3), 3.00 (s,3).

B. In a similar manner, the following compounds of formula (Ia) areprepared:

2-(2-hydroxy-5-amidinophenoxy)-4-(3-(diethylamino-carbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-methoxy-5-amidinophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-ethoxy-5-amidinophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-phenoxy-5-amidinophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-chloro-5-amidinophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-methyl-5-amidinophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-t-butyl-5-amidinophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-carboxy-5-amidinophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxycarbonyl-5-amidinophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(2-diethylaminocarbonyl-5-amidinophenoxy)-4-(3-(diethylaminocarbonyl)phenoxy)-7-methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-amidinophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)-7-(1-methylethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-hydroxy-5-amidinophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(2-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-methoxy-5-amidinophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-7-(1-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-ethoxy-5-amidinophenoxyl-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxyl-7-benzyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-phenoxy-5-amidinophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-(4-sulfonylphenyl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-chloro-5-amidinophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-7-(2-methylsulfonyl)ethyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-methyl-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxyl-7-(sulfonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-(2-t-butyl-5-amidinophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxyl-7-(indolin-3-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-amidinophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy-7-(imidazol-4-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(2-carboxy-5-amidinophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-7-(hydroxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-benzyloxycarbonyl-5-amidinophenoxy)-5-amino-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-(1-hydroxyethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-diethylaminocarbonyl-5-amidinophenoxy)-5-amino-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-7-(aminocarbonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-amino-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-7-(2-(aminocarbonyl)ethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-hydroxy-5-amidinophenoxyl-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(carboxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(2-hydroxy-5-amidinophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-7-(2-carboxyethyl)- 1,7-dihydro-6(5H)-pteridinone;

2-(2-hydroxy-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-(3-(imidazol-2-yl)phenoxy)-7-(4-aminobutyl)-1,7-dihydro-6(5H)-pteridinone;and

2-(2-hydroxy-5-amidinophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-7-(3-guanidinopropyl)-1,7-dihydro-6(5H)-pteridinone.

C. In a similar manner,2-(3-dimethylaminocarbonylphenoxy)-4-(2-benzyloxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone,a compound of formula (O), was treated to afford 0.10 g of2-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-5-amidinophenoxy)-1,7-dihydro-(6(5H)-pteridinone,a compound of formula (IIa), NMR (DMSO-d₆) 9.10 (brs,2), 8.80 (brs,2),7.70 (m,2), 7.50 (dd,1), 7.20-7.40 (m,4), 7.10 (d,1), 4.90 (s,2), 3.00(s,3), 2.90 (s,3), 2.70 (s,3).

D. In a similar manner, the following compounds of formula (IIa) areprepared:

2-(3-methylphenoxy)-4-(2-methoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-chloro-5-methoxyphenoxy)-4-(2-ethoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(4-trifluoromethylphenoxy)-4-(3-methoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3,5-diaminophenoxy)-4-(3-ethoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidino-5-methylphenoxy)-4-(2-phenoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-ureidophenoxy)-4-(3-phenoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(2-chloroethyl)-5-methylphenoxy)-4-(2-chloro-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(4-ethoxycarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazol-2-yl)phenoxy)-4-12-methyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminophenoxy)-4-(3-methyl-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy-4-(2-amino-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-t-butoxycarbonylphenoxy)-4-(3-amino-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-carboxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-t-butoxycarbonyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-t-butoxycarbonyl-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-aminocarbonyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-methoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-ethoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-methoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-ethoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-phenoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-phenoxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-chloro-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-methyl-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-amino-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-amino-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-carboxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-carboxy-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-t-butoxycarbonyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-t-butoxycarbonyl-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-aminocarbonyl-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-aminocarbonyl-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-7-methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-7-(1-methylethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-amidinophenoxy)-7-(2-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-7-(1-methylpropyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-7-benzyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-methyl-4-amidinophenoxy)-7-(4-sulfonylphenyl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-amino-5-amidinophenoxy)-7-(2-methylsulfonyl)ethyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-dimethylaminocarbonylphenoxyl-4-(3-amino-4-amidinophenoxyl-7-(sulfonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-carboxy-5-amidinophenoxy)-7-(indolin-3-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-carboxy-4-amidinophenoxy)-7-(imidazol-4-yl)methyl-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-t-butoxycarbonyl-5-amidinophenoxy)-7-(hydroxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-t-butoxycarbonyl-4-amidinophenoxy)-7-(1-hydroxyethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxyl-4-(2-aminocarbonyl-5-amidinophenoxy)-7-(aminocarbonylmethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxyl-4-(3-aminocarbonyl-4-amidinophenoxy)-7-(2-(aminocarbonyl)ethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-7-(carboxymethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-7-(2-carboxyethyl)-1,7-dihydro-6(5H)-pteridinone;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-7-(4-aminobutyl)-1,7-dihydro-6(5H)-pteridinone;and

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-amidinophenoxyl-7-(3-guanidinopropyl)-1,7-dihydro-6(5H)-pteridinone.

E. In a similar manner,2-(2-benzyloxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one (0.11 g, 0.18 mmol), a compound of formula(T), was treated to afford 0.10 g2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one, a compound of (formula (Ib), NMR (DMSO-d₆)9.10 (brs,2), 8.80 (brs,2), 7.70 (m,2), 7.50 (dd,1), 7.20-7.40 (m,4),7.10 (d,12), 4.90 (s,2) 3.00 (s,3), 2.90 (s,3).

F. In a similar manner, the following compounds of formula (Ib) areprepared:

2-(2-hydroxy-5-amidinophenoxy)-4-(3-(diethylamino-carbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-methoxy-5-amidinophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-ethoxy-5-amidinophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-phenoxy-5-amidinophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-chloro-5-amidinophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-methyl-5-amidinophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-t-butyl-5-amidinophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-carboxyl-5-amidinophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxycarbonyl-5-amidinophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-diethylaminocarbonyl-5-amidinophenoxy)-4-(3-(diethylaminocarbonyl)phenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-amidinophenoxy)-4-(5-methyl-3-(dimethyl-aminocarbonyl)phenoxy)-7-methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-hydroxy-5-amidinophenoxy)-4-(5-trifluoromethyl-3-(dimethylaminocarbonyl)phenoxyl)-7-(1-methylethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-methoxy-5-amidinophenoxy)-4-(5-methoxy-3-(dimethylaminocarbonyl)phenoxy)-7-(2-methylpropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-ethoxy-5-amidinophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-7-(1-methylpropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-phenoxy-5-amidinophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-benzyl-5H-pyrimido4, 5-b! 1,4!oxazin-6(7H)-one;

2-(2-chloro-5-amidinophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-7-(4-sulfonylphenyl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-methyl-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxyl-7-(sulfonylmethyl)-5H-pyrimido4,5-b 1,4!oxazin-6(7H)-one;

2-(2-t-butyl-5-amidinophenoxy)-4-(5-(dimethylaminoethyl.3-(dimethylaminocarbonyl)phenoxy)-7-(indolin-3-yl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-amidinophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-7-(imidazol-4-yl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-carboxy-5-amidinophenoxy)-4-(5-carboxy-3-(dimethylaminocarbonyl)phenoxy)-7-(hydroxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-benzyloxycarbonyl-5-amidinophenoxy)-4-(5-ethoxycarbonyl-3-methylphenoxy)-7-(1-hydroxyethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-diethylaminocarbonyl-5-amidinophenoxy)-4-(5-dimethylamino-3-(imidazolin-2-yl)phenoxy)-7-(aminocarbonylmethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-amino-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-3-(imidazol-2-yl)phenoxy)-7-(2-(aminocarbonyl)ethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-hydroxy-5-amidinophenoxy)-4-(5-(dimethylaminoethyl.3-(dimethylaminocarbonyl)phenoxyl-7-(carboxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-hydroxy-5-amidinophenoxy)-4-(5-(2-ethoxycarbonylethyl)-3-(tetrahydropyrimidin-2-yl)phenoxy)-7-(2-carboxyethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(2-hydroxy-5-amidinophenoxy)-4-(5-(dimethylaminocarbonyl)methyl-(3-(imidazol-2-yl)phenoxy)-7-(4-aminobutyl)-5H-pyrimido4,5-b 1,4!oxazin-6(7H)-one; and

2-(2-hydroxy-5-amidinophenoxy)-4-(5-(dimethylaminoethyl-3-(dimethylaminocarbonyl)phenoxyl-7-(3-guanidinopropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one.

G. In a similar manner,2-(3-dimethylaminocarbonylphenoxy)-4-(2-benzyloxy-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one, a compound of formula (X), is treated toafford2-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one, a compound of formula (IIb).

H. In a similar manner, the following compounds of formula (IIb) areprepared:

2-(3-methylphenoxy)-4-(2-methoxy-5-amidinophenoxy)-5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-one;

2-(3-chloro-5-methoxyphenoxyl-4-(2-ethoxy-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(4-trifluoromethylphenoxy)-4-(3-methoxy-5-amidinophenoxyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3,5-diaminophenoxy)-4-(3-ethoxy-5-amidinophenoxy)-5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-one;

2-(3-guanidino-5-methylphenoxy)-4-(2-phenoxy-5-amidinophenoxy)-5H-pyrimido4,5-b!1,4!oxazin-6(7H)-one;

2-(3-ureidophenoxy)-4-(3-phenoxy-5-amidinophenoxy)-5H-pyrimido 4,5-b!1,4!oxazin-6(7H)-one;

2-(3-(2-chloroethyl)-5-methylphenoxy)-4-(2-chloro-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-bromo-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(4-ethoxycarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazol-2-yl)phenoxy)-4-(2-methyl-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminophenoxy)-4-(3-methyl-4-amidinophenoxy-5H-pyrimido4,5-b!1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy-4-(2-amino-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-t-butoxycarbonylphenoxy)-4-(3-amino-4-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-carboxy-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-carboxy-4-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-t-butoxycarbonyl-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-t-butoxycarbonyl-4-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-aminocarbonyl-5-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

52-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-aminocarbonyl-4-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-5H-pyrimido4,5-b!1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-7-methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-(1-methylimidazolin-2-yl)phenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-7-(1-methylethyl)-5H-pyrimido4, 5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxyl-4-(3-bromo-5-amidinophenoxy)-7-(2-methylpropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-7-(1-methylpropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-methyl-5-amidinophenoxy)-7-benzyl-5H-pyrimido4,5-b!1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-methyl-4-amidinophenoxy)-7-(4-sulfonylphenyl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(2-amino-5-amidinophenoxy)-7-(2-methylsulfonyl)ethyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-dimethylaminocarbonylphenoxy)-4-(3-amino-4-amidinophenoxy)-7-(sulfonylmethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-carboxy-5-amidinophenoxy)-7-(indolin-3-yl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-carboxy-4-amidinophenoxy)-7-(imidazol-4-yl)methyl-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxyl-4-(2-t-butoxycarbonyl-5-amidinophenoxy)-7-(hydroxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-t-butoxycarbonyl-4-amidinophenoxy)-7-(1-hydroxyethyl)-5H-pyrimido-4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-aminocarbonyl-5-amidinophenoxy)-7-(aminocarbonylmethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-aminocarbonyl-4-amidinophenoxy)-7-(2-(aminocarbonyl)ethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-7-(carboxymethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(3-dimethylamino-4-amidinophenoxy)-7-(2-carboxyethyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one;

2-(3-guanidinophenoxy)-4-(2-dimethylamino-5-amidinophenoxy)-7-(4-aminobutyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one; and

2-(3-guanidinophenoxyl-4-(3-dimethylamino-4-amidinophenoxy)-7-(3-guanidinopropyl)-5H-pyrimido4,5-b! 1,4!oxazin-6(7H)-one.

EXAMPLE 2

This example illustrates the preparation of representativepharmaceutical compositions for oral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-(6(5H)-pteridinone:

    ______________________________________                                        A.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                     Lactose             79.5%                                                     Magnesium stearate   0.5%                                                     ______________________________________                                    

The above ingredients are mixed and dispensed into hard-shell gelatincapsules containing 100 mg each.

    ______________________________________                                        B.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                     Magnesium stearate  0.9%                                                      Starch              8.6%                                                      Lactose             79.6%                                                     PVP (polyvinylpyrrolidine)                                                                        0.9%                                                      ______________________________________                                    

The above ingredients with the exception of the magnesium stearate arecombined and granulated using water as a granulating liquid. Theformulation is then dried, mixed with the magnesium stearate and formedinto tablets with an appropriate tableting machine.

    ______________________________________                                        C.      Ingredients                                                           ______________________________________                                        Compound of the invention                                                                            0.1     g                                              Propylene glycol       20.0    g                                              Polyethylene glycol 400                                                                              20.0    g                                              Polysorbate 80         1.0     g                                              Water                  q.s. 100                                                                              mL                                             ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity ofwater is then added with stirring to provide 100 mL of the solutionwhich is filtered and bottled.

    ______________________________________                                        D.      Ingredients     % wt./wt.                                             ______________________________________                                        Compound of the invention                                                                         20.0%                                                     Peanut Oil          78.0%                                                     Span 60              2.0%                                                     ______________________________________                                    

The above ingredients are melted, mixed and filled into soft elasticcapsules.

    ______________________________________                                        E.    Ingredients        % wt./wt.                                            ______________________________________                                        Compound of the invention                                                                          1.0%                                                     Methyl or carboxymethyl cellulose                                                                  2.0%                                                     0.9% saline          q.s. 100 mL                                              ______________________________________                                    

The compound of the invention is dissolved in the cellulose/salinesolution, filtered and bottled for use.

EXAMPLE 3

This example illustrates the preparation of a representativepharmaceutical formulation for parenteral administration containing acompound of the invention, or a pharmaceutically acceptable saltthereof, e.g.,2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone:

    ______________________________________                                        Ingredients                                                                   ______________________________________                                        Compound of the invention                                                                            0.02    g                                              Propylene glycol       20.0    g                                              Polyethylene glycol 400                                                                              20.0    g                                              Polysorbate 80         1.0     g                                              0.9% Saline solution   q.s. 100                                                                              mL                                             ______________________________________                                    

The compound of the invention is dissolved in propylene glycol,polyethylene glycol 400 and polysorbate 80. A sufficient quantity of0.9% saline solution is then added with stirring to provide 100 mL ofthe I.V. solution which is filtered through a 0.2μ membrane filter andpackaged under sterile conditions.

EXAMPLE 4

This example illustrates the preparation of a representativepharmaceutical composition in suppository form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                         1.0%                                                      Polyethylene glycol 1000                                                                         74.5%                                                      Polyethylene glycol 4000                                                                         24.5%                                                      ______________________________________                                    

The ingredients are melted together and mixed on a steam bath, andpoured into molds containing 2.5 g total weight.

EXAMPLE 5

This example illustrates the preparation of a representativepharmaceutical formulation for insufflation containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,2-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone:

    ______________________________________                                        Ingredients           % wt./wt.                                               ______________________________________                                        Micronized compound of the invention                                                                 1.0%                                                   Micronized lactose    99.0%                                                   ______________________________________                                    

The ingredients are milled, mixed, and packaged in an insufflatorequipped with a dosing pump.

EXAMPLE 6

This example illustrates the preparation of a representativepharmaceutical formulation in nebulized form containing a compound ofthe invention, or a pharmaceutically acceptable salt thereof, e.g.,2-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                         0.005%                                                    Water              89.995%                                                    Ethanol            10.000%                                                    ______________________________________                                    

The compound of the invention is dissolved in ethanol and blended withwater. The formulation is then packaged in a nebulizer equipped with adosing pump.

EXAMPLE 7

This example illustrates the preparation of a representativepharmaceutical formulation in aerosol form containing a compound of theinvention, or a pharmaceutically acceptable salt thereof, e.g.,2-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-5-amidinophenoxy)-1,7-dihydro-6(5H)-pteridinone:

    ______________________________________                                        Ingredients        % wt./wt.                                                  ______________________________________                                        Compound of the invention                                                                        0.10%                                                      Propellant 11/12   98.90%                                                     Oleic acid         1.00%                                                      ______________________________________                                    

The compound of the invention is dispersed in oleic acid and thepropellants. The resulting mixture is then poured into an aerosolcontainer fitted with a metering valve.

EXAMPLE 8 (In vitro assay for Factor Xa, Thrombin and Tissue PlasminogenActivator)

This assay demonstrates the activity of the compounds of the inventiontowards factor Xa, thrombin and tissue plasminogen activator. Theactivities were determined as an initial rate of cleavage of the peptidep-nitroanilide by the enzyme. The cleavage product, p-nitroaniline,absorbs at 405 nm with a molar extinction coefficient of 9920M⁻¹ cm⁻¹.

Reagents and Solutions

Dimethyl sulfoxide (DMSO) (Baker analyzed grade).

Assay buffer

50 mM TrisHCl, 150 mM NaCl, 2.5 mM CaCl₂, and 0.1% polyethylene glycol6000, pH 7.5.

Enzymes (Enzyme Research Lab.)

1. Human factor Xa stock solution: 0.281 mg/mL in assay buffer, storedat -80° C. (working solution (2×): 106 ng/mL or 2 nM in assay buffer,prepare prior to use).

2. Human thrombin stock solution: Stored at -80° C. (working solution(2×): 1200 ng/mL or 40 nM in assay buffer, prepare prior to use).

3. Human tissue plasminogen activator (tPA) (Two chains, Sigma) stocksolution: 1 mg/mL, stored at -80° C. (working solution (2×): 1361 ng/mLin assay buffer, prepare prior to use).

Chromogenic substrates (Pharmacia Hepar Inc.)

1. S2222 (FXa assay) stock solution: 6 mM in dH₂ O, store at 4° C.(working solution (4×): 656 μM in assay buffer).

2. S2302 (Thrombin assay) stock solution: 10 mM in dH₂ O, stored at 4°C. (working solution (4×): 1200 μM in assay buffer).

3. S2288 (tPA assay) stock solution: 10 mM in dH₂ O, stored at 4° C.(working solution (4×): 1484 μM in assay buffer).

(All substrate working solutions were prepared on assay day 5.)

Standard inhibitor compound stock solution

5 mM in DMSO, stored at -20° C.

Test compounds (compounds of the invention) stock solutions

10 mM in DMSO, stored at -20° C.

Assay procedure

Assays were performed in 96-well microtiter plates in a total volume of200 μl. Assay components were in final concentration of 50 mM TrisHCl,150 mM NaCl, 2.5 mM CaCl₂, 0.1% polyethylene glycol 6000, pH 7.5, in theabsence or presence of the standard inhibitor or the test compounds andenzyme and substrate at following concentrations: (1) 1 nM factor Xa and164 μM S2222; (2) 20 nM thrombin and 300 μM S2302; and (3) 10 nM tPA and371 μM S2288. Concentrations of the standard inhibitor compound in theassay were from 5 μM to 0.021 μM in 1 to 3 dilution. Concentration ofthe test compounds in the assay typically were from 10 μM to 0.041 μM in1 to 3 dilution. For potent test compounds, the concentrations used inthe factor Xa assay were further diluted 100 fold (100 nM to 0.41 nM) or1000 fold (10 nM to 0.041 nM). All substrate concentrations used areequal to their K_(m) values under the present assay conditions. Assayswere performed at ambient temperature.

The first step in the assay was the preparation of 10 mM test compoundstock solutions in DMSO (for potent test compounds, 10 mM stocksolutions were further diluted to 0.1 or 0.01 mM for the factor Xaassay), followed by the preparation of test compound working solutions(4×) by a serial dilutions of 10 mM stock solutions with Biomek 1000 (orMultiprobe 204) in 96 deep well plates as follows:

(a) Prepare a 40 μM working solution by diluting the 10 mM stock 1 to250 in assay buffer in 2 steps: 1 to 100, and 1 to 2.5.

(b) Make another five serial dilutions (1:3) of the 40 μM solution (600μl for each concentration). A total of six diluted test compoundsolutions were used in the assay.

Standard inhibitor compound (5 mM stock) or DMSO (control) went throughthe same dilution steps as those described above for test compounds.

The next step in the assay was to dispense 50 μl of the test compoundworking solutions (4×) (from 40 uM to 0.164 uM) in duplicate tomicrotiter plates with Biomek or MP204. To this was added 100 μl ofenzyme working solution (2×) with Biomek or MP204. The resultingsolutions were incubated at ambient temperature for 10 minutes.

To the solutions was added 50 μl of substrate working solution (4×) withBiomek or MP204.

The enzyme kinetics were measured at 405 nm at 10 seconds intervals forfive minutes in a THERMOmax plate reader at ambient temperature.

Calculation of K_(i) of the test compounds

Enzyme rates were calculated as mOD/min based on the first two minutesreadings. The IC₅₀ values were determined by fitting the data to thelog-logit equation (linear) or the Morrison equation (non-linear) withan EXCEL spread-sheet. Ki values were then obtained by dividing the IC₅₀by 2. Routinely, Ki(factor Xa) values less than 3 nM were calculatedfrom the Morrison equation.

Compounds of the invention, when tested in this assay, demonstrated theselective ability to inhibit human factor Xa and human thrombin.

EXAMPLE 9 (In vitro assay for Human Prothrombinase)

This assay demonstrates the ability of the compounds of the invention toinhibit prothrombinase. Prothrombinase (PTase) catalyzes the activationof prothrombin to yield fragment 1.2 plus thrombin with meizothrombin asthe intermediate. This assay is an end point assay. Activity of theprothrombinase is measured by activity of thrombin (one of the reactionproducts) or by the amount of thrombin formed/time based on a thrombinstandard curve (nM vs mOD/min). For determination of IC₅₀ (PTase) of thecompounds of the invention, PTase activity was expressed by thrombinactivity (mOD/min).

Materials

Enzymes

1. Human factor Va (Haematologic Technologies Inc., Cat#HCVA-0110)working solution: 1.0 mg/mL in 50% glycerol, 2 mM CaCl₂, stored at -20°C.

2. Human factor Xa (Enzyme Res. Lab. cat#HFXa1011) working solution:0.281 mg/mL in assay buffer (without BSA), stored at -80° C.

3. Human prothrombin (FII) (Enzyme Res. Lab., Cat#HP1002) workingsolution: Diluted FII to 4.85 mg/mL in assay buffer (without BSA),stored at -80° C. Phospholipid (PCPS) vesicles

PCPS vesicles (80%PC, 20%PS) were prepared by modification of the methodreported by Barenholz et al., Biochemistry (1977), Vol. 16, pp.2806-2810.

Phosphatidyl serine (Avanti Polar Lipids, Inc., Cat#840032)

10 mg/mL in chloroform, purified from brain, stored -20° C. undernitrogen or argon.

Phosphatidyl Choline (Avanti Polar Lipids, Inc., Cat#850457)

50 mg/ml in chloroform, synthetic 16:0-18:1 Palmitoyl-Oleoyl, stored at-20° C. under nitrogen or argon.

Spectrozyme-TH (American Diagnostica Inc., Cat#238L, 50 μmoles, storedat room temperature) working solution: Dissolved 50 μmoles in 10 mL dH₂O.

BSA (Sigma Chem Co., Cat #A-7888, FractionV, RIA grade).

Assay buffer: 50 mM TrisHCl, pH 7.5, 150 mM NaCl, 2.5 mM CaCl₂, 0.1% PEG6000 (BDH), 0.05% BSA (Sigma, Fr.V, RIA grade).

For one plate assay, prepare the following working solutions

1. Prothrombinase complex

(a) 100 μM PCPS (27.5 μl of PCPS stock (4.36 mM) diluted to final 1200μl with assay buffer.

(b) 25 nM Human factor Va: 5.08 μl of Va stock (1 mg/mL) was diluted tofinal 1200 μl with assay buffer.

(c) 5 pM Human factor Xa: Dilute Xa stock (0.281 mg/mL) 1:1,220,000 withassay buffer. Prepare at least 1200 μl.

Combine equal volumes (1100 μl) of each component in the order of PCPS,Va and Xa. Let stand at ambient temperature for 5 to 10 minutes and useimmediately or store in ice (bring to ambient temperature before use).

2. 6 μM Human prothrombin (FII): dilute 124 μL of FII stock (4.85 mg/mL)to final 1400 μL with assay buffer.

3. 20 mM EDTA/Assay buffer: 0.8 mL of 0.5M EDTA (pH 8.5) plus 19.2 mLassay buffer.

4. 0.2 mM Spectrozyme-TH/EDTA buffer: 0.44 mL of SPTH stock (5 mM) plus10.56 mL of 20 mM EDTA/assay buffer.

5. Test compounds (compounds of the invention):

Prepare a working solution (5×) from 10 mM stock (DMSO) and make aseries of 1:3 dilution. Compounds were assayed at 6 concentrations induplicate.

Assay conditions and procedure

Prothrombinase reaction was performed in final 50 μL of mixturecontaining PTase (20 uM PCPS, 5 nM hFVa, and 1 pM hFXa), 1.2 uM humanfactor II and varied concentration of the test compounds (5 μM to 0.021μM or lower concentration range). Reaction was started by addition ofPTase and incubated for 6 minutes at room temperature. Reaction wasstopped by addition of EDTA/buffer to final 10 mM. Activity of thrombin(product) was then measured in the presence of 0.1 mM of Spectrozyme-THas substrate at 405 nm for 5 minutes (10 seconds intervals) at ambienttemperature in a THEROmax microplate reader. Reactions were performed in96-well microtiter plates.

In the first step of the assay, 10 μl of diluted test compound (5×) orbuffer was added to the plates in duplicate. Then 10 μl of prothombin(hFII) (5×) was added to each well. Next 30 μl PTase was added to eachwell, mix for about 30 seconds. The plates were then incubated atambient temperature for 6 minutes.

In the next step, 50 μl of 20 mM EDTA (in assay buffer) was added toeach well to stop the reaction. The resulting solutions were then mixedfor about 10 seconds. Then 100 μl of 0.2 mM spectrozyme was added toeach well. The thrombin reaction rate was then measured at 405 nm for 5minutes at 10 seconds intervals in a Molecular Devices microplatereader.

Calculations

Thrombin reaction rate was expressed as mOD/min. using OD readings fromthe five minute reaction. IC₅₀ values were calculated with the log-logitcurve fit program.

The compounds of the invention demonstrated the ability to inhibitpro-thrombinase when tested in this assay.

EXAMPLE 10 (In vivo assay)

The following assay demonstrates the ability of the compounds to act asanti-coagulants.

Male rats (250-330 g) were anesthetized with sodium pentobarbital (90mg/kg, i.p.) and prepared for surgery. The left carotid artery wascannulated for the measurement of blood pressure as well as for takingblood samples to monitor clotting variables (prothrombin time (PT) andactivated partial thromboplastin time (aPTT)). The tail vein wascannulated for the purpose of administering the test compounds (i.e.,the compounds of the invention and standards) and the thromboplastininfusion. The abdomen was opened via a mid-line incision and theabdominal vena cava was isolated for 2-3 cm distal to the renal vein.All venous branches in this 2-3 cm segment of the abdominal vena cavawere ligated. Following all surgery, the animals were allowed tostabilize prior to beginning the experiment. Test compounds wereadministered as an intravenous bolus (t=0). Three minutes later (t=3), a5-minute infusion of thromboplastin was begun. Two minutes into theinfusion (t=5), the abdominal vena cava was ligated at both the proximaland distal ends. The vessel was left in place for 60 minutes, afterwhich it was excised from the animal, slit open, the clot (if any)carefully removed, and weighed. Statistical analysis on the results wasperformed using a Wilcoxin-matched-pairs signed rank test.

The compounds of the invention, when tested in this assay, demonstratedthe ability to inhibit the clotting of blood.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made and equivalentsmay be substituted without departing from the true spirit and scope ofthe invention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A compound selected from the group consisting ofthe following formulae: ##STR7## wherein: A is --N(R⁵)--;Z¹ and Z² areindependently --O--, --N(R⁵)-- or --OCH₂ --; R¹ and R⁴ are eachindependently hydrogen, halo, alkyl, --OR⁸, --C(O)OR⁸, --C(O)N(R⁸)R⁹,--N(R⁸)R⁹, --N(R⁸)C(O)R⁹, or --N(H)S(O)₂ R¹¹ ; R² is --C(NH)NH₂,--C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹¹, --C(NH)N(H)C(O)R⁸, --C(NH)N(H)S(O)₂R¹¹, or --C(NH)N(H)C(O)N(H)R⁸ ; R³ is halo, alkyl, haloalkyl,haloalkoxy, cyano, ureido, guanidino, --OR⁸, --C(NH)NH₂, --C(NH)N(H)OR⁸,--C(O)N(R⁸)R⁹, --R¹⁰ --C(O)N(R⁸)R⁹, --CH(OH)C(O)N(R⁸)R⁹, --N(R⁸)R⁹,--R¹⁰ --N(R⁸)R⁹, --C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --N(R⁸)C(O)R⁸,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁵ ishydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy,alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R⁶ is hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl,--C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --C(O)--R¹⁰ --N(R⁸)R⁹,--R¹⁰ --C(O)R⁸, --R¹⁰ --C(O)N(R⁸)N(R⁸)R⁹, --R¹⁰ --C(R)⁸)(OR⁹)--R¹⁰--N(R⁸)(R⁹), --C(R⁸)(OR⁸)C(O)OR⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂,--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --C(R⁸)N(R⁸)R⁹)C(O)OR⁸, --C(R⁸)(OR⁸)R⁹,--R¹⁰ --N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(O)OR¹¹, --R¹⁰ --N(R⁸)C(O)R⁹, --R¹⁰--N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)S(O)₂ R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹,--R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)N(R⁸)R⁹, --R¹⁰--N(R⁸)--R¹⁰ --C(R⁸)N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --N(R⁸)S(O)R⁹, --R¹⁰ OR⁸,--R¹⁰ --ON(R⁸)C(NR⁸ N(R⁸)R⁹, --R¹⁰ --OS(O)₂ OR⁸, --R¹⁰ --P(O)(OR⁸)R⁹,--R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --P(O)(OR⁸)₂, --R¹⁰ --SR⁸, --R¹⁰ --S--R¹⁰--C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)R⁹, --R¹⁰ --S--R¹⁰--C(R⁸)N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)C(O)OR⁸, --R¹⁰ --S--R¹⁰--N(R⁸)C(O)R⁸, --R¹⁰ --S--S--R¹⁰ --C(R⁸)N(R⁸)R⁹)C(O)OR⁸, --R¹⁰--SC(O)N(R⁸)R⁹, --R¹⁰ --SC(S)N(R⁸)R⁹, --R¹⁰ --S(O)R⁸, --R¹⁰ --S(O)₂ R¹¹,--R¹⁰ --S(O)OR⁸, --R¹⁰ --S(O)₂ OR⁸, --R¹⁰ --S(O)₂ N(R⁸)R⁹, --R¹⁰--S(O)(NR⁸)R⁹ ; or R⁶ is aryl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy, --OR⁸, --SR⁸, --N(R⁸)R⁹, --C(O)OR⁸,--C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is aralkyl(optionally substituted by one or more substituents selected from thegroup consisting of alkyl, halo, haloalkyl, haloalkoxy, --OR⁸, --SR⁸,--N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); orR⁶ is heterocyclyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl,haloalkoxy, aralkyl, --OR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is heterocyclylalkyl (where theheterocyclyl radical is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy, aralkyl,--OR⁸, --SR⁸, --C(O)OR⁸, --N(R⁸)R⁹,--C(O)N(R⁸)R⁹), --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is adamantyl(optionally substituted by alkyl, halo, haloalkyl, haloalkoxy, --OR⁸,--SR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and--OP(O)(OR⁸)₂); or R⁶ is adamantylalkyl (where the adamantyl radical isoptionally substituted by alkyl, halo, haloalkyl, haloalkoxy, --OR⁸,--SR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and--OP(O)(OR⁸)₂); R⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl; eachR⁸ and R⁹ is independently hydrogen, alkyl, aryl (optionally substitutedby halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹⁰ is a straight orbranched alkylene chain; and R¹¹ is alkyl, aryl (optionally substitutedby halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); as a singlestereoisomer or a mixture thereof; or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 whereinA is --N(R⁵)--; Z¹ and Z² areboth --O--; R¹ and R⁴ are each independently hydrogen, halo or --OR⁸ ;R² is --C(NH)NH₂, --C(NH)N(H)S(O)₂ R¹¹ or --C(NH)N(H)C(O)N(H)R⁸ ; R³ isureido, guanidino, --OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --C(O)OR⁸,--N(R⁸)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionally substituted byalkyl), (1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁵ ishydrogen, alkyl, aryl (optionally substituted by halo), or aralkyl(optionally substituted halo); R⁶ is hydrogen, alkyl, --R¹⁰ --C(O)OR⁸,--R¹⁰ --C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --R¹⁰ --N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹,--R¹⁰ OR⁸, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --SR⁸, or --R¹⁰ --S(O)₂ R¹¹ ; orR⁶ is aryl (optionally substituted by one or more substituents selectedfrom the group consisting of alkyl, halo, haloalkyl, haloalkoxy and--OR⁸); or R⁶ is aralkyl (optionally substituted by one or moresubstituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy and --OR⁸); or R⁶ is heterocyclyl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy and --OR⁸); or R⁶ isheterocyclylalkyl (where the heterocyclyl radical is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy or --OR⁸); R⁷ ishydrogen, alkyl, cycloalkyl, aralkyl or aryl; each R⁸ and R⁹ isindependently hydrogen, alkyl, aryl (optionally substituted by halo,alkyl, hydroxy or alkoxy), or aralkyl (optionally substituted by halo,alkyl, hydroxy or alkoxy); R¹⁰ is a straight or branched alkylene chain;and R¹¹ is alkyl, aryl (optionally substituted by halo, alkyl, hydroxyor alkoxy), or aralkyl (optionally substituted by halo, alkyl, hydroxyor alkoxy).
 3. The compound of claim 2 whereinA is --N(R⁵)--; Z¹ and Z²are both --O--; R¹ and R⁴ are each independently hydrogen or --OR⁸ ; R²is --C(NH)NH₂ ; R³ is --C(O)N(R⁸)R⁹, (1,2)-tetrahydropyrimidinyl(optionally substituted by alkyl), (1,2)-imidazolyl (optionallysubstituted by alkyl), or (1,2)-imidazolinyl (optionally substituted byalkyl); each R⁵ is hydrogen, alkyl, aryl (optionally substituted byhalo), or aralkyl (optionally substituted halo); R⁶ is hydrogen, alkyl,--R¹⁰ --C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR9)₂, --R¹⁰--N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ OR⁸, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --SR⁸, or--R¹⁰ --S(O)₂ R¹¹ ; or R⁶ is aralkyl (optionally substituted by one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, haloalkoxy and --OR⁸); or R⁶ is imidazolylalkyl orindolylalkyl; R⁷ is hydrogen or alkyl; each R⁸ and R⁹ is independentlyhydrogen, alkyl, aryl, or aralkyl; R¹⁰ is a straight or branchedalkylene chain; and R¹¹ is alkyl or aryl.
 4. The compound of claim 3wherein:R¹ is --OR⁸ ; R² is --C(NH)NH₂ ; R³ is --C(O)N(R⁸)R⁹,(1,2)-imidazolyl (optionally substituted by methyl), or(1,2)-imidazolinyl (optionally substituted by methyl); each R⁵ ishydrogen, alkyl, aryl or aralkyl; R⁶ is hydrogen, alkyl, --R¹⁰--C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂, --R¹⁰--N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)C(O)N(R⁸ R⁹, --R¹⁰--N(R⁸)C(NR⁸)R⁹, --R¹⁰ OR⁸, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰ --SR⁸, or --R¹⁰--S(O)₂ R¹¹ ; or R⁶ is aralkyl (optionally substituted by one or moresubstituents selected from the group consisting of methyl and hydroxy);or R⁶ is imidazolylalkyl or indolylalkyl; R⁷ is hydrogen or alkyl; eachR⁸ and R⁹ is independently hydrogen, alkyl, aryl, or aralkyl; R¹⁰ is astraight or branched alkylene chain; and R¹¹ is alkyl or aryl.
 5. Thecompound of claim 4 wherein A is --N(H)--; Z¹ and Z² are both --O--; R¹is hydroxy; R² is --C(NH)NH₂ ; R³ is --C(O)N(CH₃)₂ ; and R⁴, R⁵, R⁶, andR⁷ are hydrogen.
 6. The compound of claim 5 selected from formula (I),namely,2-(2-hydroxy-5-amidinophenoxy)-4-(3-(dimethylaminocarbonyl)phenoxy)-1,7-dihydro-6(5H)-pteridinone.7. The compound of claim 5 selected from formula (II), namely,2-(3-dimethylaminocarbonylphenoxy)-4-(2-hydroxy-5-amidinophenoxy)-1,7-dihydro-6(5H)pteridinone.8. A pharmaceutical composition useful in treating a human having adisease-state characterized by thrombotic activity, which compositioncomprises a therapeutically effective amount of a compound selected fromthe group consisting of the following formulae: ##STR8## wherein: A is--N(R⁵)--;Z¹ and Z² are independently --O--, --N(R⁵)-- or --OCH₂ --; R¹and R⁴ are each independently hydrogen, halo, alkyl, --OR⁸, --C(O)OR⁸,--C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --N(R⁸)C(O)R⁹, or --N(H)S(O)₂ R¹¹ ; R²--C(NH)NH₂, --C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹¹, --C(NH)N(H)C(O)R⁸,--C(NH)N(H)S(O)₂ R¹¹, or --C(NH)N(H)C(O)N(H)R⁸ ; R³ is halo, alkyl,haloalkyl, haloalkoxy, cyano, ureido, guanidino, --OR⁸, --C(NH)NH₂,--C(NH)N(H)OR⁸, --C(O)N(R⁸)R⁹, --R¹⁰ --C(O)N(R⁸)R⁹, --CH(OH)C(O)N(R⁸)R⁹,--N(R⁸) R⁹, --R¹⁰ --N(R⁸)R⁹, --C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --N(R⁸)C(O)R⁸,(1,2)-tetrahydropyrimidinyl (optionally substituted by alkyl),(1,2)-imidazolyl (optionally substituted by alkyl), or(1,2)-imidazolinyl (optionally substituted by alkyl); each R⁵ ishydrogen, alkyl, aryl (optionally substituted by halo, alkyl, hydroxy,alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R⁶ is hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl,--C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --C(O)--R¹⁰ --N(R⁸)R⁹,--R¹⁰ --C(O)R⁸, --R¹⁰ --C(O)N(R⁸)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(OR⁹)--R¹⁰--N(R⁸)(R⁹), --C(R⁸)(OR⁸)C(O)OR⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂,--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --C(R⁸)(OR⁸)R⁹,--R¹⁰ N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(O)OR¹¹, --R¹⁰ --N(R⁸)C(O)R⁹, --R¹⁰--N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)S(O)₂ R¹¹, --R¹⁰ N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ N(R⁸)C(NR⁸)N(R⁸)N(R⁸)R⁹, --R¹⁰ --N(R⁸)--R¹⁰C(R⁸)N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --N(R⁸)S(O)R⁹, --R¹⁰ OR⁸, --R¹⁰--ON(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰ --OS(O)₂ OR⁸, --R¹⁰ --P(O)(OR⁸)R⁹, --R¹⁰--OP(O)OR⁸)₂, --R¹⁰ --P(O)(OR⁸)₂, --R¹⁰ --SR⁸, --R¹⁰ --S--R¹⁰ --C(O)OR⁸,--R¹⁰ --S--R¹⁰ --N(R⁸)R⁹, --R¹⁰ --S--R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰--S--R¹⁰ --N(R⁸)C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)C(O)R⁸, --R¹⁰ --S--S--R¹⁰--C(R⁸)(N(R⁸)R⁹ C(O)OR⁸, --R¹⁰ --SC(O)N(R⁸)R⁹, --R¹⁰ --SC(S)N(R⁸)R⁹,--R¹⁰ --S(O)R⁸, --R¹⁰ --S(O)₂ R¹¹, --R¹⁰ --S(O)OR⁸, --R¹⁰ --S(O)₂ OR⁸,--R¹⁰ --S(O)₂ N(R⁸)R⁹, --R¹⁰ --S(O)(NR⁸)R⁹ ; or R⁶ is aryl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy, --OR⁸, --SR⁸,--N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); orR⁶ is aralkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl,haloalkoxy, --OR⁸, --SR⁸, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is heterocyclyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,halo, haloalkyl, haloalkoxy, aralkyl, --OR⁸, --C(O)OR⁸, --N(R⁸)R⁹,--C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); or R⁶ isheterocyclylalkyl (where the heterocyclyl radical is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy, aralkyl,--OR⁸, --SR⁸,--C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹), --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); orR⁶ is adamantyl (optionally substituted by alkyl, halo, haloalkyl,haloalkoxy, --OR⁸, --SR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is adamantylalkyl (where the adamantylradical is optionally substituted by alkyl, halo, haloalkyl, haloalkoxy,--OR⁸, --SR⁸, --C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and--OP(O)(OR⁸)₂); R⁷ is hydrogen, alkyl, cycloalkyl, aralkyl or aryl; eachR⁸ and R⁹ is independently hydrogen, alkyl, aryl (optionally substitutedby halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹⁰ is a straight orbranched alkylene chain; and R¹¹ is alkyl, aryl (optionally substitutedby halo, alkyl, hydroxy, alkoxy, aralkoxy, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl), or aralkyl (optionallysubstituted by halo, alkyl, aryl, hydroxy, alkoxy, aralkyl, amino,dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl);as a singlestereoisomer or a mixture thereof; or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient thereof.
 9. Amethod of treating a human having a disease-state characterized bythrombotic activity, which method comprises administering to a human inneed thereof a therapeutically effective amount of a compound selectedfrom the group consisting of the following formulae: ##STR9## wherein: Ais --N(R⁵)--;Z¹ and Z² are independently --O--, --N(R⁸)-- or --OCH₂ --;R¹ and R⁴ are each independently hydrogen, halo, alkyl, --OR⁸,--C(O)OR⁸, --C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --N(R⁸)C(O)R⁹, or --N(H)S(O)₂ R¹¹ ;R² is --C(NH)NH₂, --C(NH)N(H)OR⁸, --C(NH)N(H)C(O)OR¹¹,--C(NH)N(H)C(O)R⁸, --C(NH)N(H)S(O)₂ R¹¹, or --C(NH)N(H)C(O)N(H)R⁸ ; R³is halo, alkyl, haloalkyl, haloalkoxy, cyano, ureido, guanidino, --OR⁸,--C(NH)NH₂, --C(NH)N(H)OR⁸, --C(O)N(R⁸)R⁹, --R¹⁰ --C(O)N(R⁸)R⁹,--CH(OH)C(O)N(R⁸)R⁹, --N(R⁸)R⁹, --R¹⁰ --N(R⁸)R⁹, --C(O)OR⁸, --R¹⁰--C(O)OR⁸, --N(R⁸)C(O)R⁸, (1,2)-tetrahydropyrimidinyl (optionallysubstituted by alkyl), (1,2)-imidazolyl (optionally substituted byalkyl), or (1,2)-imidazolinyl (optionally substituted by alkyl); each R⁵is hydrogen, alkyl, aryl (optionally substituted by halo, alkyl,hydroxy, alkoxy, aralkoxy, amino, dialkylamino, monoalkylamino, carboxy,alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, ordialkylaminocarbonyl), or aralkyl (optionally substituted by halo,alkyl, aryl, hydroxy, alkoxy, aralkyl, amino, dialkylamino,monoalkylamino, carboxy, alkoxycarbonyl, aminocarbonyl,monoalkylaminocarbonyl, or dialkylaminocarbonyl); R⁶ is hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, cycloalkyl, cycloalkylalkyl,--C(O)OR⁸, --R¹⁰ --C(O)OR⁸, --R¹⁰ --C(O)N(R⁸)R⁹, --C(O)--R¹⁰ --N(R⁸)R⁹,--R¹⁰ --C(O)R⁸, --R¹⁰ --C(O)N(R⁸)N(R⁸)R⁹, --R¹⁰ --C(R⁸)(OR⁹)--R¹⁰--N(R⁸)(R⁹), --C(R⁸)(OR⁸)C(O)OR⁹, --R¹⁰ --C(R⁸)(C(O)OR⁹)₂,--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --C((R⁸)(OR⁸)R⁹, --R¹⁰ --N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(O)OR¹¹, --R¹⁰ --N(R⁸)C(O)R⁹,--R¹⁰ --N(R⁸)C(NR⁸)R¹¹, --R¹⁰ --N(R⁸)S(O)₂ R¹¹, --R¹⁰--N(R⁸)C(O)N(R⁸)R⁹, --R¹⁰ --N(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰--N(R⁸)C(NR⁸)N(R⁸)N(R⁸)R⁹, --R¹⁰ --N(R⁸)--R¹⁰ --C(R⁸)(N(R⁸)R⁹)C(O)OR⁸,--R¹⁰ --N(R⁸)S(O)R⁹, --R¹⁰ --OR⁸, --R¹⁰ ON(R⁸)C(NR⁸)N(R⁸)R⁹, --R¹⁰--OS(O)₂ OR⁸, --R¹⁰ --P(O)(OR⁸)R⁹, --R¹⁰ --OP(O)(OR⁸)₂, --R¹⁰--P(O)(OR⁸)₂, --R¹⁰ --SR⁸, --R¹⁰ --S--R¹⁰ --C(O)OR⁸, --R¹⁰ --S--R¹⁰--N(R⁸)R⁹, --R¹⁰ --S--R¹⁰ --C(R⁸)(N(R⁹)C(O)OR⁸, --R¹⁰ --S--R¹⁰--N(R⁸)C(O)OR⁸, --R¹⁰ --S--R¹⁰ --N(R⁸)C(O)R⁸, --R¹⁰ --S--S--R¹⁰--C(R⁸)(N(R⁸)R⁹)C(O)OR⁸, --R¹⁰ --SC(O)N(R⁸)R⁹, --R¹⁰ --SC(S)N(R⁸)R⁹,--R¹⁰ --S(O)R⁸, --R¹⁰ --S(O)₂ R¹¹, --R¹⁰ --S(O)OR⁸, --R¹⁰ --S(O)₂ OR⁸,--R¹⁰ --S(O)₂ N(R⁸)R⁹, --R¹⁰ --S(O)(NR⁸)R⁹ ; or R⁶ is aryl (optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy, --OR⁸, --SR⁸,--N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); orR⁶ is aralkyl (optionally substituted by one or more substituentsselected from the group consisting of alkyl, halo, haloalkyl,haloalkoxy, --OR⁸, --SR⁸, --N(R⁸)R⁹, --C(O)OR⁸, --C(O)N(R⁸)R⁹, --S(O)₂OR⁸ and --OP(O)(OR⁸)₂); or R⁶ is heterocyclyl (optionally substituted byone or more substituents selected from the group consisting of alkyl,halo, haloalkyl, haloalkoxy, aralkyl, --OR⁸, --C(O)OR⁸, --N(R⁸)R⁹,--C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); or R⁶ isheterocyclylalkyl (where the heterocyclyl radical is optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, halo, haloalkyl, haloalkoxy, aralkyl, --OR⁸, --SR⁸,--C(O)OR⁸, --N(R⁸)R⁹, --C(O)N(R⁸)R⁹), --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); orR⁶ is adamantyl (optionally substituted by alkyl, halo, haloalkyl,haloalkoxy, alkyl, halo, haloalkyl, haloalkoxy, --OR⁸, --SR⁸, --C(O)OR⁸,--N(R⁸)R⁹, --C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); or R⁶ isadamantylalkyl (where the adamantyl radical is optionally substituted byalkyl, halo, haloalkyl, haloalkoxy, --OR⁸, --SR⁸, --C(O)OR⁸, --N(R⁸)R⁹,--C(O)N(R⁸)R⁹, --S(O)₂ OR⁸ and --OP(O)(OR⁸)₂); R⁷ is hydrogen, alkyl,cycloalkyl, aralkyl or aryl; each R⁸ and R⁹ is independently hydrogen,alkyl, aryl (optionally substituted by halo, alkyl, hydroxy, alkoxy,aralkoxy, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl); R¹⁰ isa straight or branched alkylene chain; and R¹¹ is alkyl, aryl(optionally substituted by halo, alkyl, hydroxy, alkoxy, aralkoxy,amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl), oraralkyl (optionally substituted by halo, alkyl, aryl, hydroxy, alkoxy,aralkyl, amino, dialkylamino, monoalkylamino, carboxy, alkoxycarbonyl,aminocarbonyl, monoalkylaminocarbonyl, or dialkylaminocarbonyl);as asingle stereoisomer or a mixture thereof; or as a pharmaceuticallyacceptable salt thereof.